ARCHER: Dacomitinib (D; PF-00299804) versus erlotinib (E) for advanced (adv) non-small cell lung cancer (NSCLC)—A randomized double-blind phase III study.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. TPS7615-TPS7615 ◽  
Author(s):  
Michael J. Boyer ◽  
Pasi A. Janne ◽  
Tony Mok ◽  
Kenneth John O'Byrne ◽  
Luis G. Paz-Ares ◽  
...  
Keyword(s):  
Phase Ii ◽  
Kras Mutation ◽  
Objective Response ◽  
Phase Iii ◽  
Rank Test ◽  
Double Blind ◽  
Mutation Status ◽  
Log Rank Test ◽  
Ecog Ps ◽  
Kras Mutation Status

TPS7615 Background: D is a highly selective irreversible small molecule inhibitor of all catalytically active members of the HER (human epidermal growth factor receptor) family of tyrosine kinases. In a randomized phase II trial in patients (pts) who had received 1–2 prior systemic therapy regimens for adv NSCLC, D demonstrated significantly longer progression-free survival (PFS) vs. E in the overall population (12.4 vs. 8.3 weeks; HR=0.66, P=0.012), with benefit consistent across several clinical and molecular subgroups. Median PFS in the KRAS wild-type (WT) subgroup was 16.1 vs. 8.3 weeks for D and E, respectively (HR=0.55, P=0.006). Methods: Based on phase II data, a randomized, double-blinded phase III clinical trial (ARCHER; NCT01360554) was designed to compare the efficacy of D with E in two co-primary populations of pts with adv NSCLC: (a) all enrolled pts with adv NSCLC, and (b) pts with KRAS WT NSCLC. Pts with locally adv/metastatic pathologically confirmed NSCLC, radiologically measurable disease, 1 or 2 prior chemotherapy regimens, ECOG PS 0–2, and tissue available for molecular analysis will be randomized to receive D 45 mg or E 150 mg orally once daily. As of Jan 31, 2012, 117 of a planned 800 pts have been enrolled. The primary endpoint is PFS. Secondary endpoints include overall survival, objective response rate, duration of response, safety and tolerability, and pt-reported outcomes of health-related quality of life and disease-/treatment-related symptoms. Study design provides 90% and 80% power to detect ≥33% and ≥45% improvement in PFS in all pts receiving D vs. E, and in pts with KRAS W T NSCLC, respectively, and HR ≤0.75 and ≤0.69 using a 1-sided stratified log-rank test at a significance level of 0.015 and 0.01, respectively. The final primary analysis stratified log-rank test will include ECOG PS, KRAS mutation status and EGFR mutation status as stratification factors. The sample sizes above will also allow the assessment of OS in the co‑primary populations with adequate power. Post-hoc analyses will be performed to explore EGFR, HER family, and KRAS mutation status, as well as other tumor-derived biomarkers collected from all pts in this trial.

KRAS mutation status-stratified randomized phase II trial of GEMOX with and without cetuximab in advanced biliary tract cancer (ABTC): The TCOG T1210 trial.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 4018-4018 ◽  
Author(s):  
Li-Tzong Chen ◽  
Jen-Shi Chen ◽  
Yee Chao ◽  
Chang-Sung Tsai ◽  
Yan-Shen Shan ◽  
...  
Keyword(s):  
Phase Ii ◽  
Kras Mutation ◽  
Phase Ii Trial ◽  
Locally Advanced ◽  
Phase Iii ◽  
Mutation Status ◽  
Randomized Phase Ii ◽  
Ecog Ps ◽  
The Impact ◽  
Kras Mutation Status

4018 Background: Gemcitabine/platinum combination is considered as globally acceptable standard care in patients with ABTC. Two recently published randomized trials showed adding EGFR antagonist, either erlotinib or cetuximab, does not further improve the clinical outcomes of gemcitabine/oxaliplatin (GEMOX)-treated ABTC patients. However, the impact of KRAS mutation status on the results of both studies was not properly addressed. Methods: A prospective, multicenter randomized, phase II trial to evaluate the therapeutic efficacies of adding cetuximab to GEMOX in patients with ABTC, in which eligible patients were stratified by status of KRAS mutation and ECOG PS, and tumor location then randomized to receive either GEMOX (gemcitabine 800 mg/m2, fixed-rate infusion and oxaliplatin 85 mg/m2, i.v., Q 2 weeks) or GEMOX plus cetuximab (500 mg/m2, i.v., Q 2 weeks, C-GEMOX). The primary endpoint was overall response rate (ORR). As an exploratory trial, 120 (60 per arm) patients was estimated to detect a two-tailed 10% difference in ORR (20% in GEMOX and 30% in C-GEMOX) with a significant level of a=0.2 and b=0.5. Results: Between Nov 2010 and May 2012, a total of 122 patients were accrued. The demography was male: 47.5%, median age: 60 y/o, ECOG PS 0/1: 28.7%/71.3%, IHCC/EHCC/GBC: 71.3%/16.4%/12.3%, KRAS mutation: 36.1%, with locally advanced/metastatic diseases: 32.0%/68.0%, and prior surgical resection: 41.8%. On intent-to-treat analysis, the ORR and DCR in the C-GEMOX (N=62) and GEMOX (N-60) arms was 27.3% vs 15.0% (p=0.1223) and 82.2% vs 60.0% (p=0.0090), respectively (Fisher’s exact test); while the median PFS was 7.1 vs 4.0 months (p= 0.0069) and median OS was 10.3 vs 8.8 months (p=0.4057), respectively (log-rank test). Planned subgroup analysis showed the 43 patients with KRAS mutated tumors benefited more from cetuximab therapy, with a DCR of 78.3% vs 38.1% (p=0.0132), median PFS of 7.0 vs 1.9 months (p=0.0351) and median OS of 10.3 vs 6.6 months (p=0.6924). Conclusions: Adding cetuximab significant improves the DCR and PFS of GEMOX in ABTC patients, notably in subpopulation with KRAS mutated tumors. Larger-scale phase III trial is warranted. Clinical trial information: NCT01267344.

Use of the intensity of membranous EGFR staining by immunohistochemistry to predict the efficacy of chemotherapy containing cetuximab in KRAS wild-type patients with metastatic colorectal cancer: A retrospective analysis.

2012 ◽  
Vol 30 (4_suppl) ◽  
pp. 516-516
Author(s):  
Naoki Takahashi ◽  
Yasuhide Yamada ◽  
Hirokazu Taniguchi ◽  
Kohei Akiyoshi ◽  
Yoshitaka Honma ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Kras Mutation ◽  
Objective Response ◽  
Endoscopic Biopsy ◽  
Rank Test ◽  
Wild Type ◽  
Mutation Status ◽  
Significant Difference ◽  
Kras Mutation Status

516 Background: KRAS mutation status is a strong predictive factor for anti-EGFR monoclonal antibody therapy efficacy in metastatic colorectal cancer (mCRC). In the BOND trial, objective response rates to cetuximab in irinotecan-refractory mCRC were not significantly different based on the intensity of EGFR staining by immunohistrochemistry (IHC). However, this result was not evaluated by KRAS mutation status, so we retrospectively evaluated the relationship between the efficacy of chemotherapy containing cetuximab and the intensity of membranous EGFR staining in KRAS wild type (KRAS-WT) patients. Methods: Between August 2008 and July 2011, specimens of 391 CRC patients were collected by endoscopic biopsy or surgical resection. EGFR staining by IHC and genetic screening for KRAS status were performed and intensity of EGFR staining was scored by the Guidelines for Interpreting EGFR pharmDx, DAKO. We analyzed 94 KRAS-WT patients who received combination chemotherapy with an irinotecan-regimen plus cetuximab or cetuximab monotherapy and met the following criteria: histologically proven mCRC adenocarcinoma , at least 1 previous regimen of standard fluoropyrimidine - containing chemotherapy , ECOG PS score 0-2, and adequate hepatic and renal function. Patients were classified into 2 groups by intensity of EGFR staining: (A) absence of staining and weakly to moderately positive (IHC 1+ and IHC 2+), (B) strongly positive (IHC 3+). Progression-free survival (PFS) and overall survival (OS) were estimated by the Kaplan-Meier method, and compared in Groups A and B by the log-rank test. Results: There was no significant difference in patient characteristics between the 2 groups except for primary site. The median PFS of Groups A (n=76) and B (n=18) were 5.4 months and 9.1 months (p= 0.029), the median OS was 8.1 months and 13.2 months (p=0.054) and response rate was 20.1% and 33.3%, respectively. Conclusions: In KRAS-WT patients with fluoropyrimidine-containing chemotherapy-refractory mCRC, strong intensity of EGFR staining by IHC might be predictive for efficacy of chemotherapy containing cetuximab.

Molecular and clinical predictors of outcome for cetuximab in non-small cell lung cancer (NSCLC): Data from the FLEX study

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 8007-8007 ◽  
Author(s):  
K. J. O'Byrne ◽  
I. Bondarenko ◽  
C. Barrios ◽  
C. Eschbach ◽  
U. Martens ◽  
...  
Keyword(s):  
Kras Mutation ◽  
Early Onset ◽  
Phase Iii ◽  
Clinical Predictors ◽  
Mutation Status ◽  
Landmark Analysis ◽  
Platinum Based Chemotherapy ◽  
Formalin Fixed Paraffin Embedded ◽  
The Relationship ◽  
Kras Mutation Status

8007 Background: The multinational, randomized, phase III FLEX study compared cisplatin/vinorelbine (CT) plus the EGFR- antibody, cetuximab (Erbitux), with CT alone in the 1st-line treatment of patients (pts) with advanced EGFR-expressing NSCLC and demonstrated a statistically significant OS benefit for the cetuximab combination. We hypothesized that KRAS mutation status is predictive for cetuximab efficacy and enables optimal use of cetuximab. The relationship between early-onset acne-like rash (ie rash that developed ≤21 days of treatment initiation) and OS time of pts treated with CT and cetuximab was also evaluated. Methods: Archived tumor samples from 554/1125 pts were available. Genomic DNA derived from formalin-fixed paraffin embedded tumor tissue was analyzed for KRAS using an LNA-mediated qPCR clamping assay capable of detecting oncogenic mutations at codons 12 and 13. The Kaplan-Meier method was used to estimate OS time and PFS time in pts with KRAS wild-type (wt) and mutant (mt) tumors for each treatment arm. All pts treated with cisplatin/vinorelbine plus cetuximab who were alive at 21 days were included in a landmark analysis evaluating the relationship between early-onset acne-like rash and OS time. Results: KRAS results were obtained from 379 pts. A KRAS mutation was detected in 72 (19%) pts. The comparison of the cetuximab treatment effects in pts with KRAS wt tumors and pts with KRAS mt tumors showed no marked differences with regard to OS or PFS. A total of 518 pts were included in the landmark analysis. Pts treated with cetuximab who developed early acne-like rash of any grade (grade 1–3; 56%, n=290) had a longer median OS than those without acne-like rash (n=228) (median [95% CI]: 15.0 months [12.8–16.4] vs 8.8 months [7.6–11.1]; HR [95% CI]: 0.63 [0.52–0.77]; p<0.001). Analysis of EGFR FISH is ongoing and results will be presented. Conclusions: Clinical data from the FLEX study do not support the hypothesis that KRAS mutation status is predictive for cetuximab efficacy when combined with 1st- line chemotherapy in advanced NSCLC, whereas early acne-like rash of any grade appears to be associated with better outcome in pts treated with platinum-based chemotherapy plus cetuximab in this setting. [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]

An international, randomized, placebo-controlled, double-blind phase III study (MONET1) of motesanib plus carboplatin/paclitaxel (C/P) in patients with advanced nonsquamous non-small cell lung cancer (NSCLC).

2011 ◽  
Vol 29 (18_suppl) ◽  
pp. LBA7512-LBA7512 ◽  
Author(s):  
G. Scagliotti ◽  
I. Vynnychenko ◽  
Y. Ichinose ◽  
K. Park ◽  
K. Kubota ◽  
...  
Keyword(s):  
Cox Model ◽  
Objective Response ◽  
Stage Iv ◽  
Progression Free Survival ◽  
High Rate ◽  
Phase Iii ◽  
Rank Test ◽  
Double Blind ◽  
Grade 3 ◽  
Nonsquamous Nsclc

LBA7512 Background: This study evaluated whether motesanib (a selective oral inhibitor of VEGFR 1, 2 and 3; PDGFR and Kit) plus C/P improved overall survival (OS) compared with placebo + C/P in patients (pts) with nonsquamous NSCLC and in a subset of pts with adenocarcinoma. Methods: Pts had stage IIIB/IV or recurrent nonsquamous NSCLC and no prior systemic therapy for advanced NSCLC. The study initially enrolled all histologies but was amended to exclude pts with squamous NSCLC owing to a high rate of hemoptysis. Pts were randomized 1:1 to receive up to six 3-wk cycles of C (AUC 6 mg/mL·min) and P (200 mg/m2) with either motesanib 125 mg QD (Arm A) or placebo QD (Arm B) orally continuously. The primary endpoint was OS; secondary endpoints included progression-free survival (PFS), adverse events (AEs), objective response rate (ORR) and association between placental growth factor (PLGF) change and OS. OS was evaluated using a stratified Cox model and 2-sided log-rank test (α=0.03 for nonsquamous pts and α=0.02 for adenocarcinoma pts). Results: 1090 pts with nonsquamous NSCLC were randomized (Arm A/B, n=541/549); 890 had adenocarcinoma (n=448/442). 61% were men; median age was 60 years (range 21–87); 83% had stage IV disease. At the time of analysis, 753 pts had died (608 pts with adenocarcinoma). Median follow-up was 10.6 mo. OS was not significantly improved in Arm A compared with Arm B (Table). In Arm A, PLGF analysis did not show an association with OS. The incidence of grade ≥3 AEs in Arms A/B was 73/59%. Grade ≥3 AEs occurring more frequently in Arm A than B included neutropenia (22/15%), diarrhea (9/1%), hypertension (7/1%) and cholecystitis (3/0%). The incidence of grade 5 AEs was 14/9% in Arms A/B. Conclusions: In pts with advanced nonsquamous NSCLC, treatment with motesanib + C/P did not significantly improve OS compared with C/P alone. [Table: see text]

scholarly journals P2.03b-053 Role of KRAS Mutation Status in NSCLC Patients Treated on SWOG S0819, a Phase III Trial of Chemotherapy with or without Cetuximab

2017 ◽  
Vol 12 (1) ◽  
pp. S967-S968
Author(s):  
Philipp Mack ◽  
James Moon ◽  
Roy Herbst ◽  
Edward Kim ◽  
Thomas Semrad ◽  
...  
Keyword(s):  
Kras Mutation ◽  
Phase Iii ◽  
Mutation Status ◽  
Phase Iii Trial ◽  
Nsclc Patients ◽  
Kras Mutation Status

Phase III randomized study of ipilimumab (IPI) plus dacarbazine (DTIC) versus DTIC alone as first-line treatment in patients with unresectable stage III or IV melanoma.

2011 ◽  
Vol 29 (18_suppl) ◽  
pp. LBA5-LBA5 ◽  
Author(s):  
J. D. Wolchok ◽  
L. Thomas ◽  
I. N. Bondarenko ◽  
S. O'Day ◽  
J. S. Weber ◽  
...  
Keyword(s):  
Metastatic Melanoma ◽  
Randomized Study ◽  
Survival Rates ◽  
Standard Of Care ◽  
Phase Iii ◽  
Rank Test ◽  
Double Blind ◽  
Prior Therapy ◽  
Treatment Naïve ◽  
Ecog Ps

LBA5 Background: IPI monotherapy (3mg/kg) improved overall survival (OS) in a phase III study of previously treated, unresectable or metastatic melanoma. Current study in 1st line metastatic melanoma evaluates combination of DTIC (a global standard of care) plus IPI. Methods: In this double-blind phase 3 study, patients (pts) with metastatic melanoma, ECOG PS 0/1, and no prior therapy for advanced disease, were randomized 1:1 to IPI (10 mg/kg) + DTIC (850 mg/m2) or placebo + DTIC (850 mg/m2) at Wks 1, 4, 7, 10 followed by DTIC q3 wks through Wk 22 (induction). Eligible pts received IPI or placebo q12 wks as maintenance. Primary endpoint was OS; 2-sided log-rank test was performed, stratified by baseline M stage and ECOG PS. Results: Of 502 pts, 56% had M1c disease, 40% elevated LDH, and 26% adjuvant therapy. 37% in IPI + DTIC and 65% in DTIC alone arms received 4 induction doses. A significant improvement in OS (HR=0.72; P=0.0009) and higher estimated 1, 2 and 3 yr survival rates were seen with IPI + DTIC (Table). 56% in IPI +DTIC (n=247) and 27% in DTIC alone (n=251) arms had grade 3/4 adverse events (AEs, regardless of attribution), including: elevated ALT (22% vs 1%); diarrhea (4% vs 0%); rash (1% vs 0%). No intestinal perforations or hypophysitis were noted. There were no drug-related deaths in IPI + DTIC and one in DTIC alone arm [gastrointestinal (GI) hemorrhage]. Conclusions: IPI (10mg/kg) + DTIC significantly improved OS in 1st line metastatic melanoma vs DTIC alone; durable survival and objective responses were noted in some pts after follow-up for up to 4yrs. Type of AEs was consistent with prior IPI studies; however, frequencies of some AEs differed with a higher transaminitis and lower diarrhea/colitis/ GI perforation rates than expected. No drug-related deaths were noted in IPI arm. OS benefit of IPI is confirmed in treatment-naive metastatic melanoma. [Table: see text]

Amrubicin and carboplatin with pegfilgrastim in patients with extensive-stage small-cell lung cancer (ES-SCLC): A phase II study of the Sarah Cannon Research Institute (SCRI).

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 7100-7100
Author(s):  
Dianna Shipley ◽  
John D. Hainsworth ◽  
Tarek Mekhail ◽  
John D. Zubkus ◽  
Douglas B. Flora ◽  
...  
Keyword(s):  
Phase Ii ◽  
Phase Ii Study ◽  
Randomized Study ◽  
Objective Response ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Highly Active ◽  
Impact On Survival ◽  
Elderly Japanese ◽  
Ecog Ps

7100 Background: Amrubicin is a novel anthracycline associated with high objective response rates (ORR) in patients (pts) with relapsed SCLC. Amrubicin improved the ORR and progression-free survival (PFS) in relapsed SCLC vs. topotecan, but not overall survival (OS) in a phase III study. Amrubicin with cisplatin/carboplatin for elderly Japanese pts was safe and active. We conducted a multicenter phase II study evaluating amrubicin and carboplatin in newly diagnosed ES-SCLC. Methods: Eligible pts had untreated ES-SCLC, measurable/evaluable disease (RECIST v. 1.1) and an ECOG PS <2. Pts received 4 cycles of amrubicin 30 mg/m2 on days 1-3 and carboplatin AUC=5 both IV day 1 every 21 days with restaging every 6 weeks. Pegfilgrastim 6 mg sq was administered on day 4 of each cycle. The primary endpoint was 1-year OS. Secondary endpoints included ORR, PFS, OS, and toxicity. Results: 78 pts were enrolled from 3/2010 to 7/2011. Baseline characteristics included: median age 65 yrs (range 45-84); 56% female. 64% completed 4 cycles of treatment. Eleven (14%) pts showed complete responses and 47 (60%) pts partial responses, for an ORR of 74% (95% confidence interval 65%-82%). Twelve (15%) pts had stable disease. Median PFS and OS were 5.3 and 9.5 months, respectively. The 1-year OS was 36%. Grade 3/4 myelosuppression was the most common toxicity (thrombocytopenia 44%, neutropenia 34%, febrile neutropenia 12%, anemia 26%), but was manageable. Severe non-hematologic toxicities (>5%) included hypokalemia 17%, fatigue 13%, dehydration 10%, hyponatremia 10%, pneumonia 9%, and nausea/vomiting 8%. 1 pt died from sepsis and another from aspiration pneumonia. Conclusions: First-line ES-SCLC treatment with amrubicin and carboplatin induced several complete responses and is considered highly active. Myelosuppression was managed effectively with growth factor support. These results are comparable to historical data with platinum-doublet chemotherapy. A larger randomized study would be required to best assess this regimen’s impact on survival.

Multicenter phase II trial of temsirolimus (TEM) and bevacizumab (BEV) in pancreatic neuroendocrine tumor (PNET).

2012 ◽  
Vol 30 (4_suppl) ◽  
pp. 260-260 ◽  
Author(s):  
Timothy J. Hobday ◽  
Rui Qin ◽  
Diane Lauren Reidy ◽  
Malcolm J Moore ◽  
Jonathan R. Strosberg ◽  
...  
Keyword(s):  
Phase Ii ◽  
Mtor Inhibitor ◽  
Phase Ii Trial ◽  
Objective Response ◽  
Progression Free Survival ◽  
Pancreatic Neuroendocrine Tumor ◽  
Phase Iii ◽  
Study Entry ◽  
Targeted Agents ◽  
Ecog Ps

260 Background: Recent placebo-controlled phase III trials of the mTOR inhibitor everolimus and the VEGF/ PDGF receptor inhibitor sunitinib in PNET noted improved progression-free survival (PFS). However, objective response rates (RR) with these agents are <10%. Preclinical studies suggest enhanced anti-tumor effects with combined mTOR and VEGF targeted therapy. Methods: We conducted a phase II trial of the mTOR inhibitor TEM (25 mg IV q week) and the VEGF-A monoclonal antibody BEV (10 mg/kg IV q 2 weeks) in patients (pts) with well or moderately differentiated PNET and progressive disease by RECIST within 7 months of study entry. Co-primary endpoints were RR and 6-month PFS. Planned enrollment is 50 patients, with interim analysis after the first 25 evaluable pts. Pts had no prior mTOR or VEGF targeted agents, ECOG PS 0-1, and adequate hematologic and organ function. Continued octreotide was allowed, but not required. Prior interferon, embolization, and ≤ 2 chemotherapy regimens were allowed. Results: Confirmed PR was documented in 11 of the first 25 (44%) evaluable patients. 20 of 25 (80%) patients were progression-free at 6 months. Both endpoints exceeded pre-defined criteria to continue enrollment. For 35 evaluable patients, the most common grade 3-4 adverse events attributed to therapy were leukopenia (12%), hypertension (12%), hyperglycemia (12%), mucositis (9%), and fatigue (9%). Conclusions: The combination of TEM/BEV has substantial activity in a multi-center phase II trial with RR of 44%, well in excess of single targeted agents in PNET. 6-month PFS was a notable 80% in a population of patients with RECIST criteria progression within 7 months of study entry. Accrual is ongoing. Supported by NCI N01 Contracts: 662205, 62203, 62208, 62209, 62206, 62204, 62207, 62201.

Impact of ROS1, ALK, and/or MET expression level on the therapeutic efficacy of GEMOX with and without cetuximab in ABTC: A post hoc analysis of a randomized phase II trial.

2014 ◽  
Vol 32 (3_suppl) ◽  
pp. 267-267
Author(s):  
Nai-Jung Chiang ◽  
Chiun Hsu ◽  
Jen-Shi Chen ◽  
Hiso-Hui Tsou ◽  
Yee Chao ◽  
...  
Keyword(s):  
Phase Ii ◽  
Kras Mutation ◽  
Therapeutic Efficacy ◽  
Phase Ii Trial ◽  
Mutation Status ◽  
Randomized Phase Ii ◽  
Prior Surgery ◽  
Post Hoc ◽  
The Impact ◽  
Kras Mutation Status

267 Background: Our randomized phase II trial showed adding cetuximab to GEMOX marginally improved the ORR and median PFS in ABTC patients regardless their KRAS mutation status. Recently, MET overexpression was noted in 11.7% to 16.2% of BTC, and associated with poor OS. ROS1 kinase fusion has also been detected in 8.6% of IHCC.The aim of the study is to evaluate the impact of ROS1, ALK and/or MET (RAM) overexpression on the clinical outcomes of ABTC patients. Methods: FFPE tissue sections that were prospectively collected for biomarker study from all 122 patients were subjected for determining the expression of ROS1, ALK and MET by IHC in a central laboratory. Results: Of 110 patients with enough tissue section for IHC of all three markers, 18 tumors were found to over-express ROS1 (in 9), ALK (in 5) and/or MET (in 6). One tumor over-expressed all three biomarkers. As compared with RAMlow tumors, the 18 RAMhigh tumors were significantly more of IHCC and without prior surgery, and with more frequent concurrent KRAS mutation. RAMhigh tumors was associated with significant inferior median OS than RAMlow tumors, 5.7 vs 11.8 months (p=0.04). Of the latter 92 patients, adding cetuximab improved the therapeutic efficacy of GEMOX in ABTC, with ORR of 31.8% vs 10.4% (p=0.02), DCR of 61.4% vs 37.5% (p=0.04) and median PFS of 7.0 vs 4.5 months (p=0.02). OS was only marginally affected, with median OS of 12.5 vs 10.4 months (p=0.36). The ORR in KRASwt and KRASmut patients receiving C-GEMOX and GEMOX was 34.5% vs 11.8% (p=0.04) and 26.7% vs 7.1% (p=0.33), respectively; whiles the DCR was 65.5% vs 50.0% (p=0.31) and 53.3% vs 7.1% (p=0.01), respectively, and the median PFS was 7.1 vs 5.8 months (p=0.07) and 7.0 vs 1.9 months (p=0.05), respectively. The results suggest that, the presence of KRAS mutation did not preclude the benefit of adding cetuximab to GEMOX in RAMlowsubpopulation. Conclusions: ROS1/ALK/METhigh ABTC had poor survival after C-GEMOX/GEMOX; while C-GEMOX significantly improved the ORR, DCR and PFS as compared to GEMOX alone in patients with ROS1/ALK/METlow tumors regardless their KRAS mutation status. Biomarker-driven design is warranted for future ABTC trials.

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