Activity of cetuximab (C) in head and neck squamous cell carcinoma (HNSCC) patients (pts) with PTEN loss or PIK3CA mutation treated on E5397, a phase III trial of cisplatin (CDDP) with placebo (P) or C.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 6028-6028 ◽  
Author(s):  
Barbara Burtness ◽  
Ju-Whei Lee ◽  
Donghua Yang ◽  
Fang Zhu ◽  
Joaquin J. Garcia ◽  
...  
Keyword(s):  
Proportional Hazards ◽  
Pik3ca Mutation ◽  
Progression Free Survival ◽  
Cox Proportional Hazards ◽  
Small Sample ◽  
Pten Expression ◽  
Phase Iii ◽  
Phase Iii Trial ◽  
Pik3ca Mutations ◽  
Pten Loss

6028 Background: Abnormalities in EGFR signaling targets are associated with C resistance but no biomarker of C resistance has been identified in HNSCC. We hypothesized that cases with loss of PTEN protein expression (PTEN null) or PIK3CA mutation would display C resistance in HNSCC. Methods: E5397 was a phase III trial of CDDP plus P or CDDP plus C and enrolled 117 eligible and evaluable pts. PIK3CA and PTEN were analyzed for 52 and 67 consented pts, respectively. PTEN expression (PTEN Cell Signaling Technology, Cat. 9559) was determined by automated quantitative analysis (AQUA) on the PM-2000 (HistoRx, New Haven) using a cutpoint generated in 5 HNSCC tissue microarrays, each consisting of HNSCC as well as positive (small intestine, median AQUA score 2833.2) and negative controls (breast and colon carcinoma, median AQUA score 205.5). A cutpoint of 570 provides 100% specificity, 100% sensitivity, and identified 30% of the HNSCCs as PTEN null, consonant with the literature. The 3 most common PIK3CA mutations (E542K and E545K in exon 9 and H1047R in exon 20) were determined by BEAMing (Inostics, Heidelberg, Germany). Response, overall survival (OS) and progression-free survival (PFS) were compared between PTEN null or PIK3CA mutated pts and all others. Log rank and multivariable Cox proportional hazards modeling were used to calculate p values. Results: 23/67 (34%) tumors were PTEN null and 2/52 (4%) had PIK3CA mutations (E542K and E545K). Both tumors with PIK3CA mutation had PTEN expression. No statistically significant differences in response, OS or PFS were noted in this small sample. However, among PTEN expressing/PIK3CA WT pts, median PFS increased to 4.2 months (m) for C (N=22) from 2.9 m for P (N=26) (Wald p=0.07), compared with 4.6 m for C (N=12) and 3.5 m for P (n=13) among the PTEN null/PIK3CA mutated (Wald p=0.60). Conclusions: The PTEN loss or PIK3CA mutation signature warrants further investigation as a predictor of C resistance.

BRAF, PIK3CA, and PTEN status and benefit from cetuximab (CET) in the treatment of advanced colorectal cancer (CRC): Results from NCIC CTG/AGITG CO.17.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 3515-3515 ◽  
Author(s):  
Derek J. Jonker ◽  
Christos Stelios Karapetis ◽  
Christopher J. O'Callaghan ◽  
Celia Marginean ◽  
John Raymond Zalcberg ◽  
...  
Keyword(s):  
Cox Model ◽  
Pik3ca Mutation ◽  
Progression Free Survival ◽  
Pten Expression ◽  
Phase Iii ◽  
Wild Type ◽  
Braf Mutations ◽  
Colorectal Tumour ◽  
Mutation Status ◽  
Pik3ca Mutations

3515 Background: CET, a monoclonal antibody targeting the epidermal growth factor receptor, improves overall survival (OS) and progression free survival (PFS) in patients (pts) with KRAS wild-type (WT) chemotherapy refractory CRC. BRAF and PIK3CA mutation status, and PTEN expression levels may further predict benefit from CET therapy. Methods: Available colorectal tumour samples were analyzed from a phase III trial of CET plus best supportive care (BSC) vs BSC alone (NEJM 2007; 357(20)). BRAF and PIK3CA mutations (MUT) identified in tumour-derived DNA using a high resolution melting analysis to identify amplicons with mutations were confirmed by sequencing. PTEN expression by immunohistochemistry (IHC) was performed on tissue microarrays constructed from available tumour blocks. For each biomarker, prognostic (treatment independent) effects were assessed in patients on the BSC alone arm. Predictive effects (benefit from CET) on OS and PFS among all patients and those in the KRAS wild-type subset were examined using a Cox model with tests for treatment-biomarker interaction, adjusting for covariates. Results: Of 401 pts assessed for BRAF status (70% of CO17 population), 13(3%) had mutations. Of 407 pts assessed for PIK3CA status (71% of CO17 population), 61(15%) had mutations. Of 205 pts assessed for PTEN (36% of CO17 population), 148(72%) were negative for IHC expression. No biomarker was prognostic for OS or PFS, and none were predictive of benefit from CET, either in the whole study population or the KRAS WT subset. Conclusions: In chemotherapy-refractory CRC, neither PIK3CA mutation status nor PTEN expression were predictive of benefit from CET therapy. BRAF mutations are uncommon in this setting. Larger sample sizes would be required to determine if BRAF status is predictive for CET benefit. [Table: see text]

Pharmacogenetic analysis in metastatic colorectal cancer (mCRC) patients (pts) treated with second-line irinotecan (IR)+/− cetuximab (CB): The EPIC experience

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 4022-4022
Author(s):  
D. Yang ◽  
A. Pohl ◽  
W. Zhang ◽  
G. Lurje ◽  
Y. Ning ◽  
...  
Keyword(s):  
Proportional Hazards ◽  
Progression Free Survival ◽  
Cox Proportional Hazards ◽  
Phase Iii ◽  
Rank Test ◽  
Second Line ◽  
Ca Repeat ◽  
Ras Mutation ◽  
Mutation Status ◽  
Log Rank Test

4022 Background: EPIC, a multinational phase III clinical trial with IR + CB vs IR alone in mCRC pts in the second-line setting after failure of FOLFOX demonstrated a benefit for IR+CB in progression-free survival (PFS) and response rate (RR). We evaluated functional germline polymorphisms involved in the EGFR- (EGF, EGFR), angiogenesis- (VEGF, IL-8, CXCR-2) - and drug- metabolism related genes (UGT1A1, MTHFR) for their potential role as molecular predictors for clinical outcome in pts treated with CB/IR vs. IR alone. Methods: DNA was extracted from all available formalin-fixed paraffin-embedded tumor samples from the phase III EPIC trial (US sites only). Genotyping was performed using PCR-RFLP assays and 5’ -end [g-33P] ATP’ labeled PCR-protocols. Results: 186 pts were treated either with IR/CB (arm A, 84 pts) or IR (arm B, 102 pts) only. In arm A, 11/84 pts (13%) showed CR or PR, whereas 73/84 (87%) pts had SD or PD. For arm B, 6/102 pts (6%) showed CR or PR, whereas 96/102 pts (94%) had SD or PD. Median PFS in arm A was 3.0 months (95%CI: 2.4- 4.1 months) vs 2.7 months (95%CI: 2.2–2.9 months) in arm B; median overall survival (OS) was 9.3 months (95%CI: 7.1–12.1 months) in arm A vs. 12.3 months (95%CI: 10.4- 17.9 months) in arm B. K-ras mutation status was not significantly associated with PFS or response to CB/IR in the subgroup of 186 patients. We found an EGFR-CA- repeat in intron 1 in arm A to be associated with PFS (p=0.031, log-rank test). In arm B, we found a significant association with RR (p=0.0103, Fisher's exact test) for MTHFR1298. Furthermore, MTHFR 677 (p =0.0048, log-rank test) and MTHFR 1298 (p=0.038, log-rank test) were also found to be associated with OS in arm B. In multivariate analysis, EGFR-CA-repeat was significantly associated with PFS (adjusted p= 0.023). Furthermore, MTHFR 677 and MTHFR 1298 was associated with OS (adjusted p=0.028 and 0.026, respectively, Cox-proportional hazards models), independent from K-ras mutation status, race and number of disease sites. Conclusions: Our study demonstrates the potential predictive value of polymorphisms in the EGFR- and MTHFR- gene in mCRC pts treated with IR+ CB. Further validation in additional clinical trials is necessary. [Table: see text]

Alectinib exposure-response (ER) in ALK-inhibitor naïve ALK-positive NSCLC patients: Pooled analysis across phase III studies.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e20575-e20575
Author(s):  
Kevin Smart ◽  
Joy C Hsu ◽  
Felix Jaminion ◽  
Elena Guerini ◽  
Alice Tsang Shaw ◽  
...  
Keyword(s):  
Proportional Hazards ◽  
Progression Free Survival ◽  
Pooled Analysis ◽  
Cox Proportional Hazards ◽  
Phase Iii ◽  
Alk Inhibitor ◽  
Exposure Response ◽  
Alk Positive ◽  
Nsclc Patients ◽  
Phase Iii Studies

e20575 Background: Alectinib superiority to crizotinib has been demonstrated in ALK-inhibitor naïve ALK-positive NSCLC patients (pts) in Phase III studies conducted in Japanese (J-ALEX; JapicCTI-132316) pts receiving alectinib 300 mg BID and global (ALEX; NCT02075840) and Asian (ALESIA; NCT02838420) pts receiving alectinib 600mg BID. ER analyses are undertaken to confirm the appropriate alectinib dosing regimen for the global population. Methods: A previous population PK analysis (Hsu et al, ASCO 2016) assessed PK of alectinib and major metabolite, M4, to identify factors influencing PK variability. ER analyses across the 3 Phase III studies investigated the relationship between alectinib and progression-free survival (PFS) by a Cox proportional hazards (CPH) analysis. PK simulations for alectinib 300 mg and 600 mg BID doses were conducted to determine the proportion of pts falling above and below an identified optimal PK threshold for PFS. ER for key safety events were investigated for alectinib 600 mg BID using logistic regression. Results: Alectinib PK is influenced only by body weight and not by race/ethnicity. CPH analysis demonstrated a statistically significant relationship between alectinib exposure and PFS across the 3 Phase III studies, with an improved PFS above an identified optimal PK threshold (Table). PK simulations indicate 49% and 7% of global alectinib treated patients would fall below the optimal PK threshold for 300 and 600mg BID, respectively. Alectinib 600mg BID ensures a distribution of exposures that maximize the PFS benefit while lower alectinib doses/exposures could result in reduced efficacy. Baseline tumor size (BSIZ) was shown to negatively impact PFS with larger BSIZ seen in global pts. No significant exposure-safety relationships were identified for alectinib 600mg BID. Conclusions: Alectinib 600mg BID is the most appropriate dose in the global ALK-inhibitor naïve population. Clinical trial information: NCT02075840; JapicCTI-132316; NCT02838420. [Table: see text]

Effect of baseline carbohydrate antigen 19-9 (CA19-9) level on overall survival (OS) in NAPOLI-1 trial: A phase III study of MM-398 (nal-IRI), with or without 5-fluorouracil and leucovorin (5-FU/LV), versus 5-FU/LV in metastatic pancreatic cancer (mPAC) previously treated with gemcitabine-based therapy.

2016 ◽  
Vol 34 (4_suppl) ◽  
pp. 425-425 ◽  
Author(s):  
Li-Tzong Chen ◽  
Jens T Siveke ◽  
Andrea Wang-Gillam ◽  
Richard Hubner ◽  
Shubham Pant ◽  
...  
Keyword(s):  
Overall Survival ◽  
Treatment Effect ◽  
Proportional Hazards ◽  
Objective Response ◽  
Progression Free Survival ◽  
Cox Proportional Hazards ◽  
Response To Therapy ◽  
Phase Iii ◽  
Free Survival ◽  
Previously Treated

425 Background: CA19-9 has been shown to correlate with response to therapy and OS in patients with mPAC. NAPOLI-1, a randomized phase 3 study evaluated nal-IRI, a nanoliposomal formulation of irinotecan, with or without 5-FU/LV vs 5-FU/LV in patients with mPAC previously treated with gemcitabine-based therapy. Nal-IRI+5-FU/LV significantly improved OS (primary endpoint) vs 5-FU/LV (6.1 mo vs 4.2 mo; unstratified hazard ratio [HR] = 0.67; P = 0.012). CA19-9 response (≥50% decline from baseline) was superior with nal-IRI+5FU/LV compared with 5-FU/LV (29% vs 9%; P=0.0006). Nal-IRI alone did not show a statistical improvement in survival. Methods: Patients with a recorded baseline CA19-9 measurement were divided into quartiles to evaluate the treatment effect pattern of CA19-9 from nal-IRI+5-FU/LV and 5-FU/LV arms. Quartile ranges were based on 404 available CA19-9 values from randomized patients (N=417). Unstratified Cox proportional hazards regression was used to estimate HRs and corresponding 95% CIs. Effect of baseline CA19-9 on time to response, progression-free survival, and response will be presented. Results: Of patients randomized to receive nal-IRI+5-FU/LV (n = 117) or 5-FU/LV enrolled contemporaneously (n = 119), 218 received study drug and had a baseline CA19-9 measurement. Results show a greater treatment effect on OS with higher CA19-9 level relative to 5-FU/LV. Conclusions: In patients with mPAC previously treated with gemcitabine-based therapy, nal-IRI+5-FU/LV significantly improved OS supported by progression free survival and objective response rate. The CA19-9 serum level can provide important information with regards to overall survival. Clinical trial information: NCT01494506. [Table: see text]

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]

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 .

Quality of life (QOL) predicts for progression-free survival (PFS) in patients with metastatic renal cell carcinoma (mRCC) treated with sunitinib compared to interferon-alpha (IFN-α)

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 6594-6594 ◽  
Author(s):  
D. Cella ◽  
J. Z. Li ◽  
J. C. Cappelleri ◽  
A. Bushmakin ◽  
C. Charbonneau ◽  
...  
Keyword(s):  
Proportional Hazards ◽  
Proportional Hazards Model ◽  
Kinase Inhibitor ◽  
Progression Free Survival ◽  
Cox Proportional Hazards ◽  
Cox Proportional Hazards Model ◽  
Self Report ◽  
Phase Iii ◽  
Health State ◽  
Eq Vas

6594 Background: In a recent international, randomized phase III trial, sunitinib malate, an oral multitargeted receptor tyrosine kinase inhibitor of VEGFRs, PDGFRs, KIT, RET and FLT3 with both antitumor and antiangiogenic effects, was associated with statistically superior clinical efficacy and superior health-related QOL vs. IFN-a as first-line therapy in patients with mRCC (Motzer et al, Proc ASCO 2006;24:2s [Abstract LBA3]). Here we report a substudy of baseline QOL variables predicting PFS. Methods: 750 mRCC patients were randomized 1:1 to receive either sunitinib 50 mg orally once daily in repeated 6-week cycles (4 weeks on treatment followed by 2 weeks off) or IFN-a (9 MU via subcutaneous injection 3 times weekly). QOL was measured by the Functional Assessment of Cancer Therapy-General (FACT-G), the FACT-Kidney Symptom Index's Disease-Related Symptoms subscale (FKSI-DRS), and the patient self-rated overall health state (EQ-VAS) from the EuroQol Group's EQ-5D self-report questionnaire. For all QOL endpoints, higher scores indicated better outcomes (better QOL or fewer symptoms). Cox proportional-hazards model was used to test which baseline QOL variables predict PFS while controlling for other baseline demographic and clinical factors as well as treatment. Because the three QOL scores are correlated (r=0.61–0.69), three separate univariate models were fitted. Results and Conclusions: All three baseline QOL variables were predictive of PFS: better baseline FACT-G, FKSI-DRS and EQ-VAS scores were associated with longer PFS. When QOL and other baseline variables were controlled in the models, the superior treatment effect of sunitinib on PFS remained robust and large (See the table below). [Table: see text]

Aspirin use and survival outcomes in patients (pts) with PIK3CA mutant colorectal cancer (CRC).

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 3598-3598
Author(s):  
Ben Tran ◽  
Robert N Jorissen ◽  
Jayesh Desai ◽  
Fiona Day ◽  
Lara Rachel Lipton ◽  
...  
Keyword(s):  
Survival Benefit ◽  
Proportional Hazards ◽  
Early Stage ◽  
Pik3ca Mutation ◽  
Predictive Biomarker ◽  
Outcome Data ◽  
Cox Proportional Hazards ◽  
Cancer Specific Survival ◽  
Pik3ca Mutations ◽  
Aspirin Group

3598 Background: Aspirin has an established role in preventing CRC. Recent data suggests aspirin use may also benefit a subset of pts diagnosed with CRC. In one series, the authors identified PIK3CA mutations as a potential predictive biomarker for aspirin use, reporting that PIK3CA mutant CRC pts receiving aspirin had superior cancer specific survival (CSS) compared to those not receiving aspirin (HR 0.18, p<0.001), whereas in pts with wildtype PIK3CA, aspirin had no survival impact. Our study aims to confirm the survival benefit associated with aspirin use in pts with PIK3CA mutant CRC. Methods: A cohort of CRC pts with PIK3CA mutations (Sanger sequencing) was identified. Prospectively collected clinicopathological, treatment and outcome data was available. Aspirin use was confirmed by chart review. CSS and overall survival (OS) analyses were conducted using Cox proportional hazards in univariate and multivariate settings. Recurrence free survival (RFS) analyses were limited to early stage CRC pts (Stage A-C). Statistical differences in 5-year CSS (5YS) rates were calculated using Fisher’s exact test. Results: From a cohort of 1,019 CRC pts with known PIK3CA mutation status, 121 (12%) harbored PIK3CA mutations. Of these, 112 (92%) had aspirin usage data available: 27 (24%) pts used aspirin, 85 (76%) did not. In the aspirin group, there were 22 (81%) early stage and 5 (19%) metastatic CRC pts; in the no-aspirin group, there were 59 (69%) early stage and 26 (31%) metastatic CRC pts. In univariate analyses, aspirin use was not associated with superior CSS (HR 0.57, p=0.21), OS (HR 0.83, p=0.57), or RFS (HR 0.72, p=0.57). In multivariate analyses, aspirin use was not associated with improved OS (HR 1.07, p=0.86), CSS (HR 1.04, p=0.94) or RFS (HR 0.54, p=0.34). In 69 (62%) pts with mature follow-up, there was a trend towards superior 5YS for aspirin users (69% v 42%, p=0.09), but this may reflect imbalances in stage at diagnosis. Conclusions: Our study was unable to confirm the recently reported survival benefit associated with aspirin use in pts with PIK3CA mutant CRC. Given the small numbers of pts, a modest survival benefit associated with aspirin use cannot be excluded. Analyses in an expanded cohort of early stage pts are underway.

Tumor-specific circulating cell-free DNA (cfDNA) to predict clinical outcome in BRAF V600 mutation-positive melanoma patients (pts) treated with the MEK inhibitor trametinib (T) or chemotherapy (C).

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 9020-9020 ◽  
Author(s):  
Dirk Schadendorf ◽  
Keith Flaherty ◽  
Peter Hersey ◽  
Paul D. Nathan ◽  
Claus Garbe ◽  
...  
Keyword(s):  
Proportional Hazards ◽  
Proportional Hazards Model ◽  
Progression Free Survival ◽  
Tumor Burden ◽  
Cox Proportional Hazards ◽  
Cox Proportional Hazards Model ◽  
Braf V600e ◽  
Phase Iii ◽  
Open Label ◽  
Alternative Source

9020 Background: Tumor-derived cfDNA in the blood is a potential alternative source to derive tumor mutation (mut) status and could be a useful biomarker of therapeutic response. Data from METRIC (NCT01245062), an open-label randomized Phase III study evaluating the efficacy and safety of T vs C, were used to assess: correlation between baseline tumor and cfDNA BRAF muts; correlation between baseline cfDNA levels and tumor burden (i.e., the sum of target lesion diameters); and efficacy based on baseline cfDNA BRAF mut status. Methods: BRAF mut status was established for 322 pts using an allele-specific PCR assay in tumor samples. Baseline plasma samples were available for 305/322 pts. cfDNA BRAF mut status was evaluated by Inostics GmBH using BEAMing technology. Spearman correlation coefficients were used to determine the association between cfDNA fraction (mut DNA molecules > 0.01%) and baseline tumor burden. A Cox proportional hazards model was used to assess the association between cfDNA mut status and progression-free survival (PFS). Results: The overall agreement between tumor and cfDNA BRAF V600E and V600K mut status was 77%, and 96% respectively. V600E or V600K cfDNA mut fraction did not correlate with baseline tumor burden (R=0.38 and 0.23, respectively). Benefit of T vs C was observed regardless of cfDNA BRAF mut status (HR= 0.42, 0.41, 0.47 for V600E, V600K, and not detectable (cfDNA ND) subgroups). Interestingly, cfDNA ND pts had longer PFS vs cfDNA V600E/K pts, independent of treatment (HR=0.37 for cfDNA ND vs V600E/K, p=<0.0001). For T cfDNA ND median PFS was not reached (n=52), however the first quartile was 4.5 months; for V600E (n=127) and V600K (n=21) median PFS was 3.5 and 4.4 months, respectively. For C median PFS was 3.5, 1.4, and 1.5 months for cfDNA ND (n=28), V600E (n=69), and V600K (n=7), respectively. Similarly, higher response rates were seen in cfDNA ND pts vs cfDNA V600E/K pts across both treatment arms. Conclusions: Free circulating DNA can be used to detect BRAF V600 muts. cfDNA mut fraction was not linked to tumor burden. The absence of circulating BRAF mut DNA in BRAF V600 pts may be a marker of a better outcome. Clinical trial information: NCT01245062.

PTEN loss as a predictive biomarker in head and neck squamous cell cancer (HNSCC) patients treated with cetuximab (C).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e17520-e17520 ◽  
Author(s):  
Nnamdi Eze ◽  
Christine H. Chung ◽  
Veronique Neumeister ◽  
Teresa Sandoval-Schaefer ◽  
Ju-Whei Lee ◽  
...  
Keyword(s):  
Race And Ethnicity ◽  
Proportional Hazards ◽  
Cell Cancer ◽  
Pik3ca Mutation ◽  
Predictive Biomarker ◽  
Cox Proportional Hazards ◽  
Exact Test ◽  
Pten Loss ◽  
Event Time ◽  
Biomarker Analysis

e17520 Background: No biomarker of C resistance has been identified in HNSCC. PTEN loss is present in approximately 30% of HNSCC. Biomarker analysis of the E5397 study suggested that addition of C to cisplatin in R/M HNSCC improves PFS in PTEN high/PIK3CA wild type patients but not those with PTEN loss or PIK3CA mutation. We hypothesized that PTEN testing may aid patient (pt.) selection for C therapy in HNSCC. Methods: MCC15780 was a phase II randomized trial of C plus sorafenib or C plus placebo in R/M HNSCC. 52/56 pts. in this study received C. PTEN analysis using AQUA as previously described was performed on tumor from 38 pts. Automated image capture was performed with HistoRx PM-2000 using the AQUAsition software. AQUA PTEN cut off determined as 1177 based on the first tertile.Fisher’s exact test used to compare low and high expression group. Event-time distributions estimated by Kaplan-Meier and compared using log-rank. Stratified Cox proportional hazards models used to estimate hazard ratios (HR) and test for significance for OS and PFS. All p-values are two-sided. A level of p < 0.05 is considered statistically significant. Results: 12/37 (32%) tumors were PTEN low. There was statistically significant improvement in PFS in PTEN high tumors compared to PTEN low tumors (HR (high/low) =0.33, 95% CI= (0.14, 0.75), p=0.008); and this remains significant after adjusting for age, sex, race, and ethnicity (HR (high/low) =0.27, 95% CI= (0.11, 0.67), p=0.004). Conclusions: PFS is significantly longer in PTEN high tumors compared to PTEN low tumors (HR=0.33, 95% CI= (0.14-0.75), p=0.008) in patients with R/M HNSCC treated with C. This finding remains significant after adjusting for age, sex, race, and ethnicity (HR=0.27, 95% CI= (0.11-0.67), p=0.004).This warrants PTEN analysis of specimens from larger cetuximab-based RCT. [Table: see text]

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