Type of progression in patients treated with imatinib for advanced gastrointestinal stromal tumor (GIST): A study based on the EORTC-ISG-AGITG trial 62005

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 10536-10536
Author(s):  
M. M. Van Glabbeke ◽  
J. Verweij ◽  
P. Casali ◽  
J. Zalcberg ◽  
A. Le Cesne ◽  
...  
Keyword(s):  
Phase Iii ◽  
Phase Iii Trial ◽  
Development Of Resistance ◽  
Biological Event ◽  
Baseline Factors ◽  
Exon 9 ◽  
M 12 ◽  
Exon 11 ◽  
The Impact ◽  
Initial Lesions

10536 Background: Development of resistance in GIST patients responding to targeted agents is heterogeneous, and different types of mutations may be observed in different lesions of the same patient. Progressive disease (PD) is defined as increase in size of initial lesions, occurrence of new lesions, or both (RECIST): mixed progression (MXPD), were new lesions develop when old lesions are still responding could represent a different type of biological event. We evaluated the impact of progression type and time to first PD (TTP) on survival after progression (SAP) in a randomized phase III trial comparing two doses of imatinib as first line treatment of GIST in 946 patients. Methods: PD was classified into 5 categories: PD in old lesion without new lesions (PD-), and new lesions associated with CR (CR+), PR (PR+), NC (NC+) and finally PD (PD+); MXPD was defined as CR+ or PR+. We investigated the correlations between type of PD, baseline patients’ characteristics, imatinib dose, TTP and SAP with univariate (UVA) and multivariate (MVA) analysis. Results: Currently, 516 patients with PD have been radiologically documented. PD-, CR+, PR+, NC+, and PD+ were observed respectively in 47%, 2%, 10%, 8%, and 33% of the cases. MXPD was more frequent in patients without prior chemotherapy (15% vs 8%), or with a long TTP (0–6 m: 1%; 6–12 m: 8%; 12–24 m: 12%; 24–60 m: 19%; 60+ m: 25%). MXPD was less frequent in KIT exon 9 mutants (7%) and wild types (4%) than in KIT exon 11 mutants (17%) (UVA), but this is entirely explained by their shorter TTP (MVA). No other correlation was found with imatinib dose or baseline factors. SAP was shown to increases with TTP (P<0.0001), and was independently (and adversely) affected by PD of old lesions and development of new lesions: when compared to PD- patients, TTP adjusted SAP hazard ratio for patients with new lesions were 0.28 (CR+), 1.07 (PR+), 1.32 (NC+) and 1.61 (PD+). SAP was longer after MXPD (UVA), but this is explained by their longer TTP (MVA). Conclusions: In GIST patients treated with imatinib, survival after first progression increases with time to progression and decreases with “severity” of progression. Mixed progressions occur later than other types of progression, and therefore lead to a longer further survival. [Table: see text]

Phase III trial of nilotinib versus imatinib as first-line targeted therapy of advanced gastrointestinal stromal tumors (GIST).

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 10501-10501 ◽  
Author(s):  
Jean-Yves Blay ◽  
Lin Shen ◽  
Yoon-Koo Kang ◽  
Piotr Rutkowski ◽  
Shukui Qin ◽  
...  
Keyword(s):  
Targeted Therapy ◽  
Kinase Inhibitor ◽  
Final Analysis ◽  
Phase Iii ◽  
Type I ◽  
First Line ◽  
Phase Iii Trial ◽  
Exon 9 ◽  
Exon 11 ◽  
Advanced Gist

10501^ Background: Nilotinib (N) is a Bcr-Abl, KIT, and PDGFR tyrosine kinase inhibitor. This Phase III trial compared N and imatinib (I) as first-line therapy of advanced GIST. Accrual was stopped when a futility boundary was crossed at interim analysis (IA). This final analysis of the core study examined the effect of mutation on outcomes. Methods: Patients (pts) with unresectable and/or metastatic GIST who had no prior antineoplastic therapy or had recurrence ≥6 months (mos) after adjuvant I were randomized 1:1 to open-label N 400 mg bid or I 400 mg qd (400 mg bid for KIT exon 9 mutants). The primary endpoint was progression-free survival (PFS) per adjudicated central review. Enrollment targeted 736 pts to observe 375 events, yielding 90% power to detect a hazard ratio (HR) of 0.71 (median, 28 [N] and 20 [I] mos) with two-sided 5% type I error. Prior to IA, crossover was allowed only for pts with progressive disease (PD); after IA, pts on N with or without PD were offered I. Results: At IA, the PFS HR for N vs I of >1.111 suggested a low probability of N superiority to I. Final analysis was performed in 644 pts; both PFS and OS favored I. In subgroup analysis of 401 pts who had mutational data, there was a large PFS difference favoring I in KIT exon 9 mutants, but similar PFS in KIT exon 11 mutants (Table). Based on immature data, OS favored I in all mutants. Conclusions: The IA showed N could not be superior to I for PFS in the overall population as first-line targeted therapy for pts with advanced GIST. PFS of N and I differed according to molecular subtypes, with PFSfavoring Iin KIT exon 9 mutants but roughly similar in exon 11 mutants. Clinical trial information: NCT00785785. [Table: see text]

scholarly journals Primary and Secondary Kinase Genotypes Correlate With the Biological and Clinical Activity of Sunitinib in Imatinib-Resistant Gastrointestinal Stromal Tumor

2008 ◽  
Vol 26 (33) ◽  
pp. 5352-5359 ◽  
Author(s):  
Michael C. Heinrich ◽  
Robert G. Maki ◽  
Christopher L. Corless ◽  
Cristina R. Antonescu ◽  
Amy Harlow ◽  
...  
Keyword(s):  
Growth Factor Receptor ◽  
Progression Free Survival ◽  
Clinical Results ◽  
Clinical Activity ◽  
Wild Type ◽  
Mutational Status ◽  
Imatinib Resistant ◽  
Exon 9 ◽  
Exon 11 ◽  
The Impact

PurposeMost gastrointestinal stromal tumors (GISTs) harbor mutant KIT or platelet-derived growth factor receptor α (PDGFRA) kinases, which are imatinib targets. Sunitinib, which targets KIT, PDGFRs, and several other kinases, has demonstrated efficacy in patients with GIST after they experience imatinib failure. We evaluated the impact of primary and secondary kinase genotype on sunitinib activity.Patients and MethodsTumor responses were assessed radiologically in a phase I/II trial of sunitinib in 97 patients with metastatic, imatinib-resistant/intolerant GIST. KIT/PDGFRA mutational status was determined for 78 patients by using tumor specimens obtained before and after prior imatinib therapy. Kinase mutants were biochemically profiled for sunitinib and imatinib sensitivity.ResultsClinical benefit (partial response or stable disease for ≥ 6 months) with sunitinib was observed for the three most common primary GIST genotypes: KIT exon 9 (58%), KIT exon 11 (34%), and wild-type KIT/PDGFRA (56%). Progression-free survival (PFS) was significantly longer for patients with primary KIT exon 9 mutations (P = .0005) or with a wild-type genotype (P = .0356) than for those with KIT exon 11 mutations. The same pattern was observed for overall survival (OS). PFS and OS were longer for patients with secondary KIT exon 13 or 14 mutations (which involve the KIT-adenosine triphosphate binding pocket) than for those with exon 17 or 18 mutations (which involve the KIT activation loop). Biochemical profiling studies confirmed the clinical results.ConclusionThe clinical activity of sunitinib after imatinib failure is significantly influenced by both primary and secondary mutations in the predominant pathogenic kinases, which has implications for optimization of the treatment of patients with GIST.

scholarly journals The impact of adding low-dose leucovorin to monthly 5-fluorouracil in advanced colorectal carcinoma: Results of a phase III trial

1998 ◽  
Vol 9 (5) ◽  
pp. 535-541 ◽  
Author(s):  
M.M. Borner ◽  
M. Castiglione ◽  
M. Bacchi ◽  
W. Weber ◽  
R. Herrmann ◽  
...  
Keyword(s):  
Colorectal Carcinoma ◽  
Low Dose ◽  
Phase Iii ◽  
Phase Iii Trial ◽  
Advanced Colorectal Carcinoma ◽  
The Impact

Continuous versus interruption of imatinib (IM) in responding patients with advanced GIST after three years of treatment: A prospective randomized phase III trial of the French Sarcoma Group

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 10005-10005 ◽  
Author(s):  
A. Le Cesne ◽  
I. Ray-Coquard ◽  
B. Bui ◽  
M. Rios ◽  
A. Adenis ◽  
...  
Keyword(s):  
Mutational Analysis ◽  
Progression Free Survival ◽  
Final Analysis ◽  
Phase Iii ◽  
Tumor Control ◽  
Phase Iii Trial ◽  
One Year ◽  
The Impact ◽  
Advanced Gist

10005 Background: IM the first-line targeted therapy for advanced GIST, must not be interrupted after one year (yr) in responding patients (pts) and has to be given continuously until disease progression (PD) or intolerance (Blay, Le Cesne et al, ASCO 2004 and 2005). The impact on progression free survival (PFS) of IM discontinuation in long lasting responding pts is unknown. Methods: This prospective national multicenter BFR14 study was initiated in June 2002. After 3 yrs of IM 400mg/day, pts free from progression were randomly offered to continue (C arm) or interrupt (I arm) IM, with the exception of pts initially randomized in the I arm after 1 yr of IM (32 pts). Pts allocated to the I arm could restart IM (same dose) in case of PD. Primary endpoint was PFS. Pts declining randomization proceed with IM. Results: As of december 2006, 286 pts were included in this trial and up to date, 35 non progressive pts at 3 yrs were randomized, 19 and 16 in the I anc C arm respectively. Pt characteristics were well balanced between the two arms. Nine progressions were reported after a median follow-up of 5.3 months (range 0–14) in this cohort of patients. IM reintroduction in the I arm after a re-progression allowed again a tumor control (OR or SD) in all evaluable pts so far. Conclusions: An increase in the rate of PD was observed in patients randomized after 3 years of IM. The final analysis will be performed after the randomization of 50 pts. Updated results including mutational analysis will be presented at the meeting. No significant financial relationships to disclose.

Time to secondary resistance (TSR) after interruption of imatinib: Updated results of the prospective French Sarcoma Group randomized phase III trial on long-term survival

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 10508-10508
Author(s):  
F. Duffaud ◽  
I. Ray-Coquard ◽  
B. Bui ◽  
A. Adenis ◽  
M. Rios ◽  
...  
Keyword(s):  
Treatment Interruption ◽  
Phase Iii ◽  
Tumor Control ◽  
Term Survival ◽  
Secondary Resistance ◽  
Phase Iii Trial ◽  
Resistance Decrease ◽  
The Impact

10508 Background: We previously demonstrated that imatinib mesylate (IM, Gleevec/Glivec; Novartis Pharma) must not be interrupted after 1 and 3 years (yr) in responding patients (pts) and has to be given continuously until disease progression (PD) or intolerance. The impact of IM re-introduction at progression remains unknown regarding the impact of the interruption on the TSR. Methods: This prospective national multicenter BFR14 study was initiated in June 2002. After 1, 3, and 5 yrs of IM 400mg/day, pts free from progression were randomly offered to continue (C arm) or interrupt (I arm) IM. Pts allocated to the I arm could restart IM (same dose) in case of PD. Primary endpoint was PFS. Pts declining randomization proceed with IM. Results: As of December 2008, 415 pts were included in this trial. Fifty-eight, 50 and 12 (ongoing) non progressive pts at 1, 3 and 5 yrs respectively were randomized in the I and C arm. Pt characteristics were well balanced between the two arms. The median time to progression (TTP) were 7.3 months (m) (rate of relapse: 91% of pts) and 9.4 m (rate of relapse: 84%) in the I arms after 1 and 3 years of treatment. In contrast the median TTP were 31.4 m and not reached in the C arms after 1 and 3 yrs of IM treatment respectively. IM reintroduction in the I arm after a re-progression allowed again a tumor control in 93% (43/46) of pts. The median follow-up from randomization is 56 m and 25 m at 1 and 3 yrs respectively. TSR after randomization to IM (first progression in the C arm, 2nd progression in the I arm) was not significantly different between the two arms (the 2-yrs TSR is similar in both arms 63% and 62% in the I and C arm respectively for the 1-yr randomization, 83.5% and 84.3% for the 3-yr randomization) but the rate of secondary resistance decrease over time in both arms: 40% or relapse in the 2 yrs following the 1 yr randomization vs less than 20% or relapse in the 2 yrs following the 3-yrs randomization. Conclusions: The majority of responding pts relapsed when IM was stopped after 1 and 3 yrs of treatment but response is reinduced in 93% of patients after IM reintroduction. TSR was not significantly affected by treatment interruption in this series of pts. [Table: see text]

Everolimus plus octreotide LAR (E+O) versus placebo plus octreotide LAR (P+O) in patients with advanced neuroendocrine tumors (NET): Updated results of a randomized, double-blind, placebo-controlled, multicenter phase III trial (RADIANT-2).

2011 ◽  
Vol 29 (4_suppl) ◽  
pp. 159-159 ◽  
Author(s):  
J. C. Yao ◽  
J. D. Hainsworth ◽  
E. Baudin ◽  
M. Peeters ◽  
D. Hoersch ◽  
...  
Keyword(s):  
Cox Model ◽  
Single Agent ◽  
Informative Censoring ◽  
High Rate ◽  
Phase Iii ◽  
P Value ◽  
Phase Iii Trial ◽  
Octreotide Lar ◽  
Phase Ii Studies ◽  
The Impact

159 Background: Octreotide LAR has been the foundation of NET therapy; however, additional treatment options are needed. Everolimus, an oral inhibitor of mTOR, demonstrated promising antitumor activity in patients with NET as a single agent and in combination with octreotide LAR in two phase II studies. Methods: Patients (n = 429) with well or moderately differentiated advanced NET and history of carcinoid symptoms received oral everolimus 10 mg/d + octreotide LAR 30 mg IM q 28 days (n = 216) or placebo + octreotide LAR (n = 213). Common primary sites included the small intestine, lung, and colon. The primary endpoint was progression-free survival (PFS) per central review by RECIST. Crossover from P+O to open-label E+O was allowed at disease progression. Results: Median PFS (95% CI) with E+O was 16.4 months (13.67-21.19) vs. 11.3 months (8.44-14.59) for P+O. E+O was associated with a 23% reduction in risk of progression: HR = 0.77; 95% CI: 0.59-1.00; one-sided p-value = .026 (pre-specified significance boundary is p ≤ .0246). A high rate of informative censoring resulted in loss of power in central review results. Correcting for the informative censoring bias, the pre-specified marginal Cox model using inverse probability of censoring weights (IPCW) analysis showed a significant 5.5-month improvement in median PFS with E+O; HR = 0.60; 95% CI: 0.44-0.84, with one-sided p-value = .0014. The benefit of E+O was seen across all patient subgroups. Updated analyses of the impact of pre-study and post-progression octreotide LAR therapy will be reported. Most frequent drug-related adverse events (AEs) with E+O were stomatitis, rash, fatigue, and diarrhea; mostly grade 1-2. Grade 3-4 AEs reported in >5% were stomatitis, fatigue, diarrhea, infections, and hyperglycemia. Conclusions: In this large phase III trial, E+O provided a 5.1-month clinically meaningful increase in median PFS compared with P+O in the central adjudicated review. Correcting for the informative censoring bias, a significant PFS improvement of 5.5 months was seen, with a p value = .0014. The safety profile of E+O was acceptable. [Table: see text]

Prognostic stratification of post-docetaxel metastatic castration resistant prostate cancer (mCRPC) from a phase III randomized trial.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 4644-4644 ◽  
Author(s):  
Guru Sonpavde ◽  
Gregory Russell Pond ◽  
Stephen John Clarke ◽  
Janette L. Vardy ◽  
S. L. Wang ◽  
...  
Keyword(s):  
Prognostic Model ◽  
Risk Model ◽  
Cox Proportional Hazards ◽  
Phase Iii ◽  
Prognostic Impact ◽  
Castration Resistant Prostate Cancer ◽  
Phase Iii Trial ◽  
Neutrophil Lymphocyte Ratio ◽  
Potential Marker ◽  
The Impact

4644 Background: A prognostic model for mCRPC post docetaxel is necessary to guide therapy. We retrospectively analyzed a phase III trial enrolling progressive mCRPC following docetaxel to construct a prognostic model. Additionally, we studied the impact of neutrophil-lymphocyte ratio (NLR), a potential marker for inflammatory and immune state. Methods: A phase III trial (SUN-1120) comparing prednisone combined with sunitinib (N=584) or placebo (N=289) for mCRPC following docetaxel-based chemotherapy was evaluated. The treatment arms were combined for analysis, since no statistical difference was observed in the primary endpoint of overall survival (OS). A logarithmic transformation was applied to non-normal factors. The Kaplan-Meier method was used for OS estimation. To identify an optimal prognostic model for survival, we used a Cox proportional hazards regression methods with forward stepwise selection, stratifying for ECOG PS, progression type (PSA or radiographic) and treatment group. A risk score was calculated and patients were categorized into risk groups to assess model performance. Results: Data from patients without missing data (n=806) were used to construct an optimal model. The factors used in the model that remained individually significant in multivariate analysis were: log-LDH (HR 2.77 [95% CI=2.23, 3.44], p<0.001), hemoglobin (0.81 [0.76, 0.87], p<0.001), log-NLR (1.63 [1.38, 1.92], p<0.001), >1 organ involved (1.53 [1.24, 1.88], p<0.001), log-alkaline phosphatase (1.14 [1.01, 1.30], p=0.041) and log-PSA (1.07 [1.00, 1.13], p=0.036). No clear cutpoints were identified; thus, these prognostic factors were used to group patients into 3 equally sized risk categories. Low, medium and high risk patients (n=268-270 per group) had median (95% CI) OS estimates of 23.7 (21.4-not reached), 13.5 (11.6-15.8) and 7.3 (6.3-8.4) months, respectively. Conclusions: A prognostic risk model with readily available variables significantly discriminated between outcomes in post-docetaxel mCRPC and may provide valuable information in future studies. High NLR was associated with an independent poor prognostic impact, and warrants prospective validation.

Analysis of prognostic factors in patients with advanced relapsed/refractory NSCLC: Cox regression analysis of a randomized phase III trial comparing docetaxel and paclitaxel poliglumex (PPX)

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 7040-7040 ◽  
Author(s):  
P. Bonomi ◽  
C. Langer ◽  
M. O’Brien ◽  
K. O’Byrne ◽  
B. Bandstra ◽  
...  
Keyword(s):  
Overall Survival ◽  
Cox Regression ◽  
Performance Status ◽  
Stage Iv ◽  
Tumor Stage ◽  
Phase Iii ◽  
Line Treatment ◽  
Phase Iii Trial ◽  
Cox Regression Analysis ◽  
The Impact

7040 Background: A phase III trial compared PPX to docetaxel as 2nd-line treatment in pts with relapsed/refractory advanced NSCLC (STELLAR 2). While overall survival was similar between arms, the need for supportive measures to manage the effects of myelosuppression was significantly reduced in the PPX arm. The current analysis was performed to evaluate determinants of survival in the 2nd-line treatment of NSCLC. Methods: STELLAR 2 enrolled 849 pts, 427 on PPX and 422 on docetaxel; all patients were included in the analysis. Randomization between the study arms was stratified by tumor stage, performance status (PS), start of frontline chemotherapy (< 4 mo vs more than 4 mo), gender, and prior taxane therapy. Univariate and multivariate Cox regression analyses were performed to evaluate the impact of baseline characteristics on overall survival (OS). Results: At randomization, 29% of pts had received prior taxane, 14% were PS2, 80% had stage IV disease, and 31% had started frontline therapy within the prior 4 months. Risk factors significantly affecting survival as determined by multivariate analysis are listed in the table . These factors were consistent when treatment was added to the model. Prior exposure to taxane was not predictive of survival; tumor stage was a significant univariate predictor (p=0.0349), but had relatively less impact in the multivariate model. Conclusion: These analyses identified several factors associated with reduced survival benefit from standard second line therapy. Consequently, alternative treatment strategies may be necessary in patients with poor prognosis. For example, more tolerable agents may enhance the benefit/toxicity ratio in these patients. [Table: see text] [Table: see text]

Impact of p16 status on the QOL effects of chemoradiation for locally advanced oropharynx cancer: Results of TROG 02.02.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 5571-5571 ◽  
Author(s):  
Jolie Ringash ◽  
Richard Fisher ◽  
Lester J. Peters ◽  
Brian O'Sullivan ◽  
Andy Trotti ◽  
...  
Keyword(s):  
Oropharyngeal Cancer ◽  
Locally Advanced ◽  
Phase Iii ◽  
Phase Iii Trial ◽  
Significant Difference ◽  
Ecog Ps ◽  
The Impact ◽  
Subsequent Time Point

5571 Background: We report the impact of p16 status on quality of life (QOL) for patients with stage III or IV (excluding T1-2N1 and M1) squamous cell carcinoma of the oropharynx (OPC) treated with concurrent chemoradiotherapy in a large international phase III trial (TROG 02.02/HeadSTART). Methods: The 861 patients accrued received definitive radiotherapy (RT) (70 Gy/7 weeks) concurrently with 3 cycles of either cisplatin (100mg/m2) or cisplatin (75 mg/m2) plus tirapazamine (290 mg/m2/day) by random assignment, as previously described. QOL was measured with the FACT-H&N at baseline, 2,6,12, 23 and 38 months. No significant difference in overall or subscale QOL score change from baseline was observed between arms at any subsequent time point; results for the oropharynx subgroup by p16 status are reported for both treatment arms combined. Results: Of 853 eligible participants, 465 had OPC, for whom p16 status could be determined in 206. Of 179 who received adequate RT (≥ 60 Gy, no major deviations) and completed baseline QOL, 104 were p16+ and 79 were p16-. p16+ patients had better baseline ECOG PS, lower T-category, higher N-category, were younger and were less likely to be current smokers. Baseline mean FACT-H&N score was statistically and clinically significantly better in p16+ patients (111 vs. 102, p=0.001). The drop in QOL from baseline to 2 months was more severe in p16+ cases (-20.4 vs -9.1, p=0.001), resulting in an equalization of 2 month scores (p16+: 90.6, p16-: 93.6, p=0.16). At 6 and 12 months post-treatment, no difference in score changes from baseline by p16 status was seen (6 mo, p16+: -6.2, p16 -:-1.2, p=0.22; 12 mo, p16 +: -0.3, p16 -: +2.0, p=0.82). Conclusions: p16 associated oropharyngeal cancer has been shown to be a distinct entity with different demographic features. In our study, such patients exhibited better baseline QOL and a more severe drop immediately after treatment, but did not differ in long-term QOL response to the effects of aggressive concurrent chemoradiation. Given the favorable prognosis of p16-associated oropharyngeal cancer, efforts to reduce the QOL burden of treatment are warranted.

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