Gastrointestinal Stromal Tumor Pts Research Articles

Safety, pharmacokinetics (PK), and clinical activity of bezuclastinib + sunitinib in previously-treated gastrointestinal stromal tumor (GIST): Results from part 1 of the phase 3 Peak study.

11537 Background: Patients with GIST often relapse after first line therapy with imatinib due to secondary resistance mutations in KIT. As the KIT mutation targeting profiles of bezuclastinib (type I TKI) and sunitinib are distinct and complementary, when combined they inhibit a broad spectrum of secondary KIT mutations. In a prior Phase 1b/2a study (NCT02401815), the combination of the original formulation (Form. A) of bezuclastinib + sunitinib had an acceptable safety profile and was associated with clinical activity at the RP2D (Wagner, JAMA Oncol 2021;7(9):1343-50). An optimized formulation (Form. B) of bezuclastinib with improved bioavailability was developed to reduce pill burden for GIST pts. PK and safety results from the Part 1a lead-in of Peak (NCT05208047) have been previously presented (Wagner, CTOS 2022, P320). Herein we intend to report comprehensive clinical results from Part 1a including duration of therapy, initial response assessment and updated safety. Methods: Peak, a randomized Phase 3, open-label study, aims to evaluate efficacy and safety of bezuclastinib + sunitinib vs sunitinib in pts with imatinib-resistant or intolerant GIST. In Part 1a of the 3-part study, bezuclastinib (Form. B) dosing was escalated in serial cohorts based on PK results until the target exposure, comparable to those achieved at the RP2D established in the Phase 1b/2a study, was achieved. Key inclusion: adult with locally advanced, metastatic and/or unresectable GIST, ≥1 measurable lesion according to modified RECIST v1.1, and ECOG PS 0 to 2. Results: Part 1a enrolled 19 pts. Five pts (Cohort 1) received the starting dose of once daily (QD) bezuclastinib 300 mg+ sunitinib 37.5 mg; dose was escalated to 600 mg with 14 pts receiving bezuclastinib 600 mg + sunitinib 37.5 mg. Median age - 60 yrs (range: 42-77); 68% male; 95% ECOG PS 0-1; 95% metastatic and 5% locally advanced. As of Sept 2022 data cutoff, the median (range) treatment duration was 6 weeks (3.1, 23.9). Due to AEs, one pt required dose reduction of bezuclastinib (Gr 3 diarrhea) and 1 pt discontinued (Gr 2 rash). The majority of TEAEs were low grade, with no ≥ Gr4. Most common TRAEs were diarrhea (37%), neutropenia (37%), ALT (32%) and AST (26%) increases. One pt experienced SAEs of Gr 2 neutropenia and pyrexia and Gr 3 thrombocytopenia. Steady state exposure in pts receiving QD doses of bezuclastinib 600 mg + sunitinib 37.5 mg in this study were similar to that at the RP2D established in the prior Phase 1b/2a study. Conclusions: Initial data from Peak shows an encouraging safety and tolerability profile with no unique safety signals when compared to the known safety profile for sunitinib monotherapy. A dose of bezuclastinib 600 mg QD + sunitinib 37.5 mg QD was confirmed for use in Peak study Part 2, for which enrollment is ongoing. Updated data from Part 1a, including response data, will be presented. Clinical trial information: NCT05208047 .

Outcomes of patients (pts) with advanced gastro-intestinal stromal tumors (GIST) treated with multi-kinase inhibitors other than imatinib (IM) as first-line treatment.

11532 Background: IM is the standard first-line therapy in advanced GIST, with a median progression-free survival (PFS) of 30 months. Recent multi-kinase inhibitors (MKIs) such as nilotinib, dasatinib or masitinib have been tested as first-line therapies in phase II/III studies. This might theoretically result in increased PFS (by the addition of a new line of treatment), or in early emergence of resistance to approved MKIs. Methods: A retrospective chart review was performed in GIST pts who received investigational MKIs (in phase II/III trials) as first-line treatment, followed by IM as second line. Data on demographics, molecular profile, PFS, and overall survival (OS) were collected in two French referral centers. Results: Of 47 pts, (57% females), 22 (47%) had a KIT exon 11 mutation, one a KIT exon 9 mutation (2%), one a PDGFR D842V mutation (2%). Five patients were wild-type for KIT and PDGFR. The mutational status was unknown in 18 pts (38 %). From 2005 to 2011, 21 pts (45%) received masitinib, 18 (38%) received dasatinib and 8 pts (17%) received nilotinib. Median PFS on first-line treatment was 18.9 months [95%IC: 9.0-26.0]. Median time-to-failure (TTF) with IM was 19.7 months [95%IC: 14.8-53.4]. Median time to second relapse was 50.2 months [95%IC: 31.2-92.2]. Thirty-five patients (74.5%) were dead at the end of follow-up. The median OS from time of initial diagnosis was 5.9 years [95%IC: 4.5-8.2]. Conclusions: GIST pts who received MKIs other than IM as first-line treatment and IM as second-line had a time to second relapse longer than that observed historically with IM in first line. This suggests that using MKIs other than IM in first line does not decrease IM efficacy in second line. Further comparative studies are needed to confirm these findings, but this is encouraging to further develop studies with other MKIs in the first line setting.

Activity and safety of cabozantinib in patients with gastrointestinal stromal tumor after failure of imatinib and sunitinib: EORTC phase II trial 1317 CaboGIST.

11006 Background: Gastrointestinal stromal tumor (GIST) is the most common mesenchymal malignancy of the gastrointestinal tract. Advanced GIST is treated with tyrosine kinase inhibitors (TKIs). Most patients (pts) develop resistance over time. We reported in 2013 (Van Looy CTOS) that cabozantinib (cabo), a TKI targeting KIT/MET/AXL/VEGFR, showed activity in GIST xenograft models through inhibition of tumor growth, proliferation and angiogenesis, both in imatinib-sensitive and -resistant tumors (Gebreyohannes Mol Cancer Ther 2016;15:2845-28). Cohen (Cancer Res 2015;75:2061-70) found that cabo can overcome compensatory MET signaling in GIST in vitro. EORTC 1317 assessed the safety and activity of cabo in pts who had progressed on imatinib and sunitinib. Methods: In this multi-center, open label, single arm Phase 2 study eligible metastatic GIST pts received 60 mg (freebase weight) cabo p.o./d. Primary endpoint was progression-free survival rate at wk 12, assessed by local investigator per RECIST 1.1. If at least 21 of 41 eligible and evaluable pts were progression-free at wk 12, the activity of cabo was sufficient to warrant further exploration (A’Hern one-stage design). Results: A total of 50 consenting pts were eligible and started treatment between 02/2017 and 08/2018, with 16 (32%) still continuing cabo at the database cut-off in 01/2019. The number of 3 wk treatment cycles ranges from 2-28+. Among the first 41 eligible and evaluable pts, 24 were progression-free at wk 12, satisfying the study decision rule. Among all 50 pts, 30 were progression-free at wk 12 (60%, 95% confidence interval (CI) 45-74%). A total of 7 pts achieved a confirmed partial response (PR) (14%, 95%CI 6-27%) and 33 had stable disease (SD) (66%, 95%CI 51-79%). Progression as best response was seen in 9 pts (18%, 95%CI 9-31%), one was not evaluable. Disease control (PR+SD) was achieved in 40 pts (80%, 95%CI 66-90%). Median progression-free survival was 6.0 mo (95%CI 3.6-7.7). The most common cabo-related grade ≥3 adverse events were diarrhea (74%), hand-foot syndrome (58%), fatigue (46%), hypertension (46%), weight loss (38%) and oral mucositis (28%), with 33 (66%) pts requiring dose reductions, 25 (50%) treatment interruptions and no cabo-related deaths. Conclusions: EORTC 1317 met its primary endpoint, with 24/41 pts (58.5%) being progression-free at wk 12. Results of this trial confirm preclinical data and warrant further exploration of cabo in GIST. Clinical trial information: NCT02216578.

Abstract 4578: Development of a rapid clinical grade assay to detect and monitor secondary KIT mutations in circulating free DNA (cfDNA) for personalization of targeted therapy for gastrointestinal stromal tumors (GIST)

Abstract Introduction: Genotype-directed therapies are revolutionizing care for gastrointestinal stromal tumors (GIST). Somatic mutations in KIT exons (ex) 11 and 9 induce constitutive kinase activity and account for ~95% of the primary oncogenic events in KIT-driven GIST; KIT mutations correlate with prognosis and predict clinical activity of tyrosine kinase inhibitors (TKI), such as imatinib. After a median of 24 months on imatinib, 85% of patients (pts) develop resistance and progress multifocally, mostly due to secondary KIT mutations in ex 13 and/or ex 17. We describe here a rapid, clinical grade droplet digital PCR (ddPCR) assay to detect and quantify KIT mutations associated with TKI resistance in cfDNA from plasma of metastatic (met) GIST pts. Unlike allele-specific ddPCR that requires splitting input DNA into many reactions, we designed pan-ex 17 KIT assay to capture the polyclonal mutational landscape of KIT in a single reaction. Methods: Tumor and plasma samples and clinical data were collected from pts with met GIST. ddPCR assays were developed for the detection in cfDNA of all common secondary KIT mutations associated with imatinib resistance (V654A, T670I, A829P and multiple ex 17 mutations). The pan-ex 17 mutation drop-off assay uses a FAM-labeled mutant (mut) probe that spans sequences encoding amino acids 819~824, and a VIC-labeled reference probe that is shared by both wild-type (wt) and mut alleles. Common ex 17 mutations were detected via cluster separation. V654A, T670I, A829P are detected with allele-specific assays that use a FAM-labeled mut probe and a VIC-labeled wt probe. To demonstrate analytical sensitivity/specificity of each assay, ddPCR cycling conditions were optimized to yield the maximum fluorescence signal with minimal noise signal. Results: The KIT ddPCR assays detect a mutation prevalence of 0.01 - 0.05%, with a sensitivity of 5 - 50 KIT mut copies in a background of 10,000 KIT wt copies, depending on the mutation assayed, with absolute specificity. Results were validated in a pilot observational cohort of pts who were treated with imatinib and progressed, for which matching plasma (1 ml) and tumor samples were analyzed to reveal identical mutations. In a separate cohort, ddPCR results were validated by sensitive plasma NGS. Conclusions: We have developed rapid, highly sensitive, and 100% specific quantitative assays to enable plasma-based tumor genotyping for secondary KIT resistance mutations, which has been technically optimized for translation into clinical practice. Analysis of cfDNA by ddPCR can successfully detect KIT secondary mutations in met GIST pts. In an ongoing study, serial monitoring of KIT mutations in cfDNA from pts with advanced GIST should allow for early detection of secondary mutations and optimization of genotype-targeted therapeutic management. Citation Format: Adrian Marino-Enriquez, Suzanne George, Julianna Supplee, Grace Heavey, Pasi A. Janne, Chandrajit Raut, Jonathan Fletcher, George D. Demetri, Cloud P. Paweletz, Yanan Kuang. Development of a rapid clinical grade assay to detect and monitor secondary KIT mutations in circulating free DNA (cfDNA) for personalization of targeted therapy for gastrointestinal stromal tumors (GIST) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4578.

Abstract LB-039: Translational research in a phase I proof-of-concept study supports that DCC-2618 is a pan-KIT inhibitor

Abstract Background: DCC-2618 is a potent switch control inhibitor of KIT and PDGFRα kinases maintains potent inhibition of mutant forms across all exon regions in preclinical models. Gastrointestinal stromal tumor (GIST) is an important disease to achieve a proof-of-concept due to the heterogeneity of resistance mutations in KIT which emerge on treatment with approved KIT inhibitors. In later lines of therapy resistance mechanisms independent of the KIT gene have also been described. Methods: The ongoing phase 1, PK-guided dose escalation study of DCC-2618 given orally BID [28-day cycle] tested doses from 20 mg to 200 mg in patients (pts) with advanced solid tumors including GIST (NCT02571036). We report preliminary longitudinal results of plasma cell free (cf) DNA sequencing by Guardant 360 collected throughout the study and levels of circulating tumor cells (CTCs) based on a viral telomerase promoter-driven GFP expression assay. Results: To date, 24 out of 31 enrolled pts had metastatic KITm GIST refractory to standard therapy. A high, total mean exposure of DCC-2618 and its active metabolite was achieved at 100 and 150 mg BID, affording steady state Cmax >5 µM in Cycle 1. Starting with 50 mg BID dose level, concentrations of total drug exceeding IC90 of the most resistant mutations to DCC-2618 were achieved. Next-generation sequencing of plasma cfDNA revealed a total of 40 KIT mutations in 16 of 18 GIST pts at baseline. DCC-2618 led to rapid decrease and/or clearance of the heterogeneous array of KIT mutations from plasma cfDNA including exons 9, 11, 13, 14, 17, and 18. Independent of suppressed KIT mutation burden, longitudinal monitoring of cfDNA revealed changes in non-KIT oncogenic mutations which may contribute to heterogenous mechanisms of resistance. KIT mutation burden will be correlated with metabolic response assessment by PET scans and exposure to DCC-2618. CTCs have been detected in blood from all GIST patients at baseline using a non-biased assay capable of identifying sarcoma cells. Preliminary result show that CTCs with immunofluorescent detection of KIT or PDGFRα, corresponding to their respective mutational status, show 1 of 3 patterns when compared to radiologic response: most pts show relatively stable low levels at stable disease (SD), a minority of pts with prolonged SD a decline in CTCs and 2 pts with progressive disease had significant increase in KIT positive CTCs. Conclusions: DCC-2618 and its active metabolite achieved high plasma concentrations sufficient to inhibit the most resistant KIT mutations at well-tolerated exposures. Monitoring of cfDNA KIT mutation frequency demonstrates rapid clearance of a broad spectrum of KIT mutations in this heavily pretreated GIST patient population and suggests candidate resistance genes that are independent of KIT. Our data provide a first signal that CTC monitoring might represent a potential marker for tumor control in KIT mutant GIST. Citation Format: Filip Janku, Albi Razak, Michael Gordon, David Brooks, Daniel Flynn, Anu Gupta, Michael Kaufman, Cynthia Leary, Bryan Smith, Deb Westwood, Neeta Somaiah, Elena Helman, Eric Gerstenberger, Oliver Rosen, Suzanne George. Translational research in a phase I proof-of-concept study supports that DCC-2618 is a pan-KIT inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-039. doi:10.1158/1538-7445.AM2017-LB-039

Pharmacokinetic-driven phase I study of DCC-2618 a pan-KIT and PDGFR inhibitor in patients (pts) with gastrointestinal stromal tumor (GIST) and other solid tumors.

2515 Background: DCC-2618 is a potent switch control inhibitor of KIT and PDGFR kinases active in a broad range of mutations. GIST is an important disease to achieve a proof-of-concept due to the heterogeneity of KIT resistance mutations, which emerge on treatment with approved KIT inhibitors. Methods: This was a PK-guided dose escalation study of oral DCC-2618 (QD or BID q28 days) in advanced solid tumors. FDG-PET scans were used to assess changes in FDG uptake in GIST pts after 3 wks of therapy. Next generation sequencing (NGS) of plasma cell-free (cf) DNA was performed throughout the study to assess and quantify KIT and other molecular alterations in drug targets and potential mechanisms of resistance. Results: 38 pts were enrolled (30 GIST; 4 glioma; 1 mastocytosis, 3 other carcinoma) to 8 dose levels: BID doses: 20 (4 pts), 30 (4), 50 (5), 100 (6), 150 (6) and 200 mg (3); QD doses: 100 (5) and 150 mg (4). Safety of evaluable pts is as follows: G3 or G4 adverse effects (regardless of attribution and occurring in > 1 pt) included anemia (5), lipase increase (4), hypertension (2). Two of the G3/4 lipase increase at 100 mg BID and 200 mg BID were DLTs. All G3/4 lipase increase were asymptomatic. G1/2 AEs (considered at least possibly related to DCC-2618) and occurring in ≥15% (n > 5) of pts include fatigue (12), alopecia & lipase increase (7), weight decrease (6). Starting with 50 mg BID dose level, trough concentrations of total drug exceeded the IC90 of the least sentivitive KIT mutations. Plasma concentrations > 5μM were achieved starting at 100 mg BID and the selection of the expansion phase dose is being finalized. Of 18 pts with KIT mutant GIST assessed by FDG PET, 14 (78%) had partial metabolic response per EORTC criteria. RANO/RECIST partial responses (PRs) were reported in 3 patients (1 GBM with PDGFRA/KIT amplifications and 2 GIST with Ex 11 & 17 / Ex 11 & 18 mutations, respectively). NGS of plasma cfDNA revealed 44 KIT mutations in baseline samples from 19 of 21 pts with GIST. Conclusions: DCC-2618 is well tolerated with encouraging preliminary activity in GIST pts with a broad spectrum of mutations and prior therapies. PR was also seen in a pt with GBM with PDGFRA/KIT amplifications. Clinical trial information: NCT02571036.

Clinical experience with sunitinib (SU) in patients over age 65 with metastatic gastrointestinal stromal tumors (GIST): A retrospective study from the French Sarcoma Group (FSG).

10546 Background: Elderly GIST patients (pts) represent a consistent portion of all GIST pts, but are under-represented in clinical trials. Data on benefits, tolerance of SU in elderly GIST pts and their specific outcome are very limited. Methods: Charts of elderly pts (≥ 65 yrs)treated with SU in routine clinical practice from 11 Centres of the FSG were reviewed to evaluate the efficacy and safety of SU. Results: 71 elderly GIST pts were reviewed, with a median age of 74, [distributed as 65-74, n=36; 75-84, n=30; ≥ 85, n=5], 41 (57%) men, with median ECOG-PS= 1 (0-2), and median active comorbities of 1 (0-4). SU was administered after progression on first-line Imatinib (400 mg/d for 21 pts, 400 then 800 mg/d for 45 pts) or masitinib (5 pts). SU was started at 50 mg/d 4-wks-on/2 wks-off in 37 pts (52%), at 37.5 mg daily in 32 pts (45%), and at 25 mg daily in 2 pts. All but 2 pts experienced at least one adverse event (AE). Drug related AE were mainly of grade 1 or 2 (298/388, 76%), and medically manageable. Most frequent AE were fatigue (20%), diarrhea (11%), mucositis (7%), abdominal pain (7%), hand-foot syndrome (6%), neutropenia (6%), and hypertension (5%). Permanent dose reduction was reported in 33 pts (46%). In 17 pts (24%) SU was permanently stopped due to grade 3 or 4 AE. ; this occurred within 3 months after starting SU in 10 pts. At a median 36 months follow-up, 53 pts progressed, and 28 pts were alive. The median PFS and OS were 10.2 (0.2-54) and 21 (0.5-77) months, respectively. Univariate analysis showed that age (≤ 80), PS (<1), WBC (≤ 4 Giga/l), Hb and Albumin have a positive impact on OS (all p < 0.04) and PFS (all p < 0.05). In multivariate analysis, Albumin and Hb had an impact on OS and PFS, PS had an impact only on OS, and WBC only on PFS. A correlation was found between comorbidities and Grade 3/4 toxicities, but no correlation between any toxicities and outcome. Conclusions: Compared to data from clinical trials, SU yields similar rates of GIST control and OS in elderly pts despite frequent dose reductions or interruptions. Since comorbidities may increase the risks of AEs, careful follow-up to assess tolerance is particularly indicated in elderly GIST pts.

Imatinib plasma concentrations during long-term effective treatment of metastatic gastrointestinal stromal tumor.

10543 Background: Imatinib concentrations at one month after the start of imatinib have shown an association with clinical benefit in pts with gastrointestinal stromal tumors (GISTs) and a significant decrease of 30% within twelve months. This retrospective study investigated imatinib plasma concentrations in pts with metastatic GISTs in a long-term (≥2 years) effective treatment. Methods: 31 metastatic GIST pts, who had been treated with imatinib for two or more years in our hospital, were enrolled in this study. 11 pts were excluded because of adjuvant setting (n=5) and rejection to concentration testing (n=6). 20 pts were included in this study. GISTs were immunohistochemically diagnosed, and radiologically assessed as effective GIST by Choi’s criteria without relapse. Results: 10 pts were male, median age was 63 years (range, 31-84), and median imatinib exposure time was 3.5 year (range, 2-12). The median plasma concentration was 1093 ng/ml (range, 417-2091) and minimal level after at least five years was 789 ng/ml. imatinib concentration has no significant correlation with age, gender, gastrectomy, leukocyte count, platelet count, serum albumin, serum creatinine, cholesterol, and duration of imatinib exposure. Body surface area (BSA) isn’t directly associated with imatinib dose; median BSA of pts taking 300mg imatinib was 1.560 m2 and that of 400mg 1.595 m2, but minimal BSA of 400mg imatinib was 1.560 m2, which is higher than the minimum of 300mg. Conclusions: Plasma concentrations of long-term (≥2 years) response pts was scattered, but one of longer-term (≥5 years) response pts were more than 789 ng/ml. Effective imatinib plasma level might be more than 789 ng/ml and 400mg imatinib may be recommended for a pt with BSA(≥1.56 m2).

Prescribing decision drivers in patients with recurrent gastrointestinal stromal tumor (GIST) previously treated with adjuvant imatinib: A retrospective chart extract-based approach.

e21515 Background: Adjuvant imatinib (IM) is the standard of care for primary resectable GIST. However, little is known about prescribing habits following disease recurrence. This study identifies main prescribing decision drivers in recurrent GIST pts following completion of adjuvant IM treatment. Methods: Using an online data collection system, clinical information was retrieved on 410 pts treated with adjuvant IM for ≥6 months for primary resectable KIT+GIST, who discontinued IM treatment, had a recurrence (while off IM), and subsequently restarted IM or initiated sunitinib. Pt-level data were collected at primary diagnosis and at first recurrence. Prescribing decision drivers were identified using logistic regression models. Physicians were also surveyed to identify factors that influence their prescribing decisions. Results: Following initial disease recurrence, 77% of pts restarted IM and 23% initiated sunitinib. IM duration at primary diagnosis was the main prescribing decision driver; pts treated with IM for a shorter period of time (≤18 months) were 7.0 times more likely to restart IM than pts with longer IM duration (p<.01). Pts who took longer (≥12 months) to develop recurrence after IM discontinuation (Odds ratio [OR]=3.4; p=<.01 ), had a low mitotic rate at recurrence (OR=2.8; p=<.01), or had a recurrence inside the gastrointestinal system (OR=2.7; p=<.01) were also more likely to be prescribed IM following recurrence. These findings were consistent with the top survey responses on factors influential to prescribing decisions after recurrence: time to develop recurrence (55%), pt risk profile (53%), and IM duration prior to recurrence (51%). Conclusions: Based on information of pts who restarted IM or initiated sunitinib, IM treatment duration at primary diagnosis, time to develop recurrence after IM discontinuation, tumor location and mitotic rate at recurrence seem to be the main prescribing decision drivers. These findings were consistent with physicians’ main factors reported to influence their prescribing decisions following recurrence.

Investigation of gastrointestinal stromal tumor (GIST) care management in GIST patients (pts) receiving short-term versus long-term imatinib (IM) adjuvant therapy: A chart review analysis.

195 Background: Although optimal duration of adjuvant IM therapy in Kit+ GIST pts is unknown, the NCCN guidelines recommend treatment for ≥36 months in high-risk pts based on clinical trials showing reduced risk of recurrence and mortality in pts receiving long-term adjuvant IM. The objective of this study was to investigate clinicians’ recurrence risk assessment and GIST management in patients receiving adjuvant IM for short- (6-12 months) vs. long-term (≥24 months) in community practice. Methods: GIST-related and treatment characteristic information on adult pts with primary resectable Kit+ GIST initiating IM ≤84 days after surgery (short-term: 411 pts; long-term: 408 pts) was collected from 320 U.S. oncologists using an online data collection form. In addition, physician prescribing patterns and perception of risk assessment and IM duration were collected. Results: Indicators of risk (tumor size, mitotic count, and tumor location) were significantly associated with IM treatment duration. Tumor rupture status did not impact IM duration, except when unknown, in which case pts had longer IM duration. About 50% of pts had not been tested for Kit mutation; 31% of physicians reported that it would not have changed therapy/management or were not aware of how results should have impacted GIST management. Among short-term pts for whom physicians reported a reason for IM discontinuation, main reasons included non-severe adverse events, completion of the 1-year treatment scheduled, economic constraint/health plan coverage change, and pts’ preference. Overall, 77.8% of surveyed physicians reported that pt risk profile drove their decision of continuing IM over an extended period of time. However, in practice 39.9% of the short-term pts and 48.8% of the long-term pts had a high risk profile as assessed by Fletcher classification; suggesting a lack of consistency between treatment related opinions and practice. Conclusions: These observed discrepancies highlight the need for standardization of risk assessment practices and education among community oncologists and pts.

1478O - Clinical Benefit with Regorafenib Across Subgroups and Post-Progression in Patients with Advanced Gastrointestinal Stromal Tumor (GIST) After Progression on Imatinib (IM) and Sunitinib (SU): Phase 3 Grid Trial Update

ABSTRACT Background Regorafenib (REG) therapy significantly improved progression-free survival (PFS) in patients (pts) with GIST after failure of both IM and SU (J Clin Oncol 2012; 30: suppl; abstr LBA10008). Results of subgroup and post-progression analyses are presented here. Methods Pts were randomized (2:1) to receive best supportive care plus either REG 160 mg or placebo (PL) po once daily (3 wks on/1 wk off). The primary endpoint was PFS. Upon progression in either arm, unblinding could occur. Pts on PL were eligible for crossover to open-label (OL) REG and progressive pts on REG were allowed to continue REG upon local physician's choice. Results GRID screened 234 pts and randomized 199 (REG: 133, PL: 66), well balanced for baseline characteristics. The PFS primary endpoint (according to RECIST) was met both per central review (median PFS 4.8 mo for REG vs. 0.9 mo for PL), and by investigator assessment (median PFS 7.4 mo for REG vs. 1.7 mo for PL). Exploratory sensitivity analyses demonstrate similar positive impact on PFS across pre-specified subgroups by number of prior systemic therapy, geographical region, age, baseline ECOG score, duration of prior treatment with imatinib, or KIT/PDGFRA mutation. Median overall survival has not been reached in either arm. Taking the double-blind and OL periods together, 188 pts received REG. Post-progression PFS per investigator assessment was 5.0 mo for pts in the PL arm who crossed over to REG (n = 56), and 4.5 mo for pts in the REG arm who continued to receive REG after unblinding (n = 41). Conclusion REG induced significant PFS benefit in GIST pts following resistance to both IM and SU across all pre-specified subgroups. Interestingly, 41 pts on REG (out of 133) whose physicians decided to continue REG after RECIST progression had an additional PFS benefit which was in the same range. This suggests that continuous kinase inhibition after progression may benefit pts by slowing tumor progression and/or that RECIST criteria for progression applied by blind central review have clinical shortcomings. Disclosure P.G. Casali: Consultant/advisory: Bayer, MSD, GSK, Infinity, Novartis, Pfizer, PharmaMar, Sanofi Honoraria: Novartis, Pfizer, PharmaMar Research funds: Amgen Dompe, Bayer, MSD, GSK, Imclone, Infinity, Lilly, Molmed, Novartis, Pfizer, PharmaMar, Sanofi. P. Reichardt: Consultant/advisory: Bayer. Y. Kang: Consultant/advisory: Bayer Research funding: Bayer. J. Blay: Honoraria: Pharmama, Novartis, Pfizer, Roche, GSK Research funding: Pharmama, Novartis, Pfizer, Roche, GSK. P. Rutkowski: Consultant/advisory: Novartis, MSD, BMS Honoraria: Novartis, Pfizer, BMS, MSD, Roche. M. Leahy: Research funding as PI for GRID study at Christie Hospital, Manchester, UK. M. von Mehren Consultant/advisory: Novartis, Pfizer, Astex; Honoraria: Novartis, Pfizer. H. Joensuu Consultant/advisory: Novartis, Boehringer-Ingelheim. A. Le Cesne Honoraria: Novartis, Pfizer, Pharmamar. P. Schoffski: Research funding: Bayer. R. Maki: Consultant/advisory: Bayer, Pfizer, Novartis; Honoraria: Bayer, Pfizer, Novartis; Research funding: Pfizer; Expert testimony: Pfizer. I. Kuss: Employment: Bayer. D. Laurent: Employment: Bayer Stock ownership: Bayer. G.D. Demetri: Consultant/advisory: Novartis, Pfizer, GSK, Roche, Deciphra (uncompensated), Infinity Research funding: Novartis, Pfizer, GSK, Infinity Expert testimony (uncompensated): Infinity, Pfizer, Novartis, Bayer. All other authors have declared no conflicts of interest.

Masitinib in imatinib-naive advanced gastrointestinal stromal tumor (GIST): Five-year follow-up of the French Sarcoma Group phase II trial.

10089 Background: Masitinib is a tyrosine kinase inhibitor that in vitro has greater activity and selectivity than imatinib against KIT. This multicenter, open label, phase 2 study evaluated efficacy and safety of masitinib as a first-line treatment of advanced GIST. Initial results with a median follow-up of 34 months, were previously reported in EJC 2010. We present here 5-year follow-up data from the same series with updated safety and survival data. Methods: Imatinib-naïve patients (pts) with inoperable, advanced GIST received oral masitinib (7.5 mg/kg/day) until progression, refusal or toxicity. Results: Thirty pts with a median age of 58 years (60% of males) were included from 06/2005 to 04/2007 in 5 institutions. At the cut-off date of 13/09/2011, 7/30 pts (23%) were still under treatment with median follow-up of 65 months and the median overall survival (OS) had not yet been reached (NR). The 5-year OS rate was 61.5% (95% CI [41.1;76.6]) (see Table). Among patients with confirmed KIT exon 11 mutation, 8/9 pts (89%) were still alive with one pt having died from non-treatment related causes (surgical complication) following a complete response while receiving masitinib. No additional progressions have been reported giving a total of 14 events (13 progressions and 1 death). Updated median PFS was 41.3 months (95% CI [17.5;53.8]).No additional grade 3/4 adverse events have been reported. Conclusions: Long term results of masitinib confirm an interesting activity with prolonged PFS and OS. The median PFS rate in masitinib compares very favorably to that of imatinib, which is reported as 18 months (JCO 26:626, 2008). The 5-year OS rates for masitinib in the overall and exon 11 populations also compare favorably to imatinib, both of which are reported at ≤50% for imatinib (JCO 26:626, 2008; JCO 28:1247, 2010). These results support the head to head comparison with imatinib in the currently ongoing phase 3 randomized clinical trial in first line advanced GIST pts. [Table: see text]

Risk of disease recurrence and mortality in gastrointestinal stromal tumor (GIST) patients receiving short-term versus long-term imatinib adjuvant therapy: A chart review analysis.

e20511 Background: The benefits of long-term (36 months) use of adjuvant imatinib (IM) in high risk GIST patients (pts) have been demonstrated in a recent multicenter, prospective clinical trial that compared efficacy and safety of 3 years vs 1 year IM treatment. However, in clinical practice, there is no consensus on the optimal IM treatment duration after surgery. The objective of this retrospective observational study was to compare the risk of recurrence and survival among primary resectable Kit positive GIST pts treated with adjuvant IM for a short vs an extended period of time in a real-world setting. Methods: Information on adult pts with primary resectable Kit positive GIST initiating imatinib ≤84 days after surgery was collected from 248 U.S. oncologists using an online data collection form. Detailed pt information following first GIST diagnosis, including demographic, GIST-related characteristics (e.g., risk profile), comorbidity profile, IM treatment characteristics, disease recurrence and mortality was collected for pts with short-term (6-12 months) and long-term IM use (≥24 months). Disease recurrence and mortality rates were estimated from the 1st surgery date to the 1st evidence of recurrence, mortality, or end of observation period. Multivariate Cox proportional hazard models were used to compare recurrence and mortality rates between short vs long term IM use pts. Results: Among the 246 short-term and 395 long-term IM pts, the median follow up was 884 and 963 days, respectively. The average age was similar [59.0 (10.4) vs 58.1 (9.5); p=.23] but short-term pts had less males [57.7% vs 69.6% (p<.01)] and a lower Miettinen risk score [0.3 vs 0.4, p< .01)] than long-term pts. Disease recurrence [7.3 vs 1.8%, (p< .01)] and mortality rates [6.9% vs 2.3%, (p < .01)] were also higher in short- vs long-term pts. The adjusted risk of recurrence was 4.77 times [95% CI: 1.98 – 11.48, (p<.01)] higher and mortality risk was 3.44 times [CI: 1.53 – 7.75, (p<.01)] higher in short- vs long-term pts. Conclusions: Use of IM over an extended period of time is associated with a reduction in long-term risk of disease recurrence and mortality.

Evaluation of hand-foot syndrome (HFS) as a potential biomarker of sunitinib (SU) efficacy in patients (pts) with metastatic renal cell carcinoma (mRCC) and gastrointestinal stromal tumor (GIST).

e21113 Background: Common side effects of tyrosine kinase inhibitors (TKIs) such as SU include HFS and related skin toxicities. SU is a multitargeted inhibitor of VEGFR, PDGFR and KIT, and is standard of care for the treatment of advanced RCC and imatinib-resistant/intolerant GIST. In this retrospective analysis, correlations between SU-associated HFS and efficacy endpoints were investigated in mRCC and GIST pts from 5 and 4 clinical trials, respectively. Methods: Analyses included data from 1,186 pts with mRCC (n=770) or GIST (n=416) who received single-agent SU at 25, 50, or 75 mg/d on an intermittent schedule (4 weeks (wk) on/2 wk off, 2 wk on/2 wk off, or 2 wk on/1 wk off: n=869; 73%) or at 37.5 mg continuous daily dosing (n=317; 27%). Median progression-free survival (PFS) and overall survival (OS) were estimated by Kaplan-Meier methods and compared between pts with vs. without HFS by log-rank test. ORR was compared by Pearson’s chi-square test. Tumor response was assessed by investigators and adverse events were recorded regularly. Multivariate, time-dependent covariate, and landmark analyses were performed. Results: Of 1,186 pts, 260 (22%) developed any-grade HFS, compared with 926 (78%) who did not. Pts with mRCC who developed HFS had significantly better ORR (66.5% vs. 31.8%), PFS (14.3 vs. 8.3 mo), and OS (38.3 vs. 18.9 mo) than pts who did not (P<0.0001). Pts with GIST who developed HFS also had significantly better ORR (22.2% vs. 10.7%), PFS (11.0 vs. 5.5 mo), and OS (35.7 vs. 16.6 mo) than pts who did not (P<0.01). SU-associated HFS remained a significant predictor of both PFS and OS in a multivariate analysis (and of OS by time-dependent covariate analysis) in both mRCC and GIST pts. In 6- and 12-wk landmark analyses, pts with mRCC but not GIST who developed HFS had significantly longer OS, with a trend toward longer PFS, than pts who did not. Conclusions: SU-associated HFS was associated with improved PFS and OS in both mRCC and GIST pts, although the landmark analysis suggests that HFS may not be a reliable biomarker of SU efficacy at early time points.

Definition of an imatinib trough concentration threshold in the treatment of advanced gastrointestinal stromal tumors (GIST).

10013 Background: Imatinib (IM) as front-line treatment has dramatically changed the evolution of GIST. Demetri et al. (JCO, 0927. 3141-7) previously showed that patients with trough IM plasma concentrations (Cmin) below 1110 ng/mL (Quartile 1) had shorter time to progression. We prospectively performed routine analysis of I in advanced GIST pts in which we investigated the relationships between Cmin and progression-free survival (PFS). Methods: A clinical database of advanced GIST pts for whom Cmin measurements has been prospectively set. The concentration decile boundary that produced the most statistically significant difference in PFS for patients with Cmin values above and below the value was defined using a log-rank test. Cox regression analysis was performed to evaluate factors associated with longer PFS. Results: We evaluated 102 patients treated by IM 400 mg/day (41 stomach, 34 small bowel and 27 other or unreported primary site localizations) with 253 trough plasma determinations. Median Cmin after steady-state was 784ng/mL (range:154-3321) with 75% inter-individual and 26% intra-patient variabilities. A Cmin threshold of 1030 ng/mL was associated with longer PFS for the whole GIST population (p=0.044). However, a Cmin threshold of 780 ng/mL was found separately for stomach (p=0.043) and small bowel localizations (p=0.049). Cox regression analysis found that Cmin above 780 ng/mL was associated with 71% reduction risk of progression (p=0.008) and that small bowel localization was associated with an increased relative risk of progression of 5.31 versus stomach localization (p=0.007). Conclusions: This analysis of IM in pts treated with 400 mg/d, allowed to define a Cmin threshold of 780 ng/ml associated with 71% reduction of progression risk for stomach and small bowel localizations of advanced GIS.

Prognostic importance of cell-cycle activity and genotype in gastrointestinal stromal tumors.

e20501 Background: Size, mitosis and locus are important for risk stratification of gastrointestinal stromal tumors (GIST). Genotype and cell cycle are suggested related to aggressiveness and progression, and considered to have prognostic impact, although most reports have analyzed expression of proteins or mRNAs. In this study, we examined the biological and prognostic values of CDK activities in primary GIST with R0 surgery. Methods: Histologic Dx was done with HE and IH. Using lysate of frozen materials from 76 pts with GIST (n=70), leiomyoma (2), schwannoma (3) and abdominal sarcoma (1), CDK-specific activities were measured by the C2P system (activities of CDK1 & CDK2). The median age was 64 yrs and 33 (45%) pts were male. The median follow-up was 37 months. Results: KIT and PDGFRA mutations were found in 57 and 7 GIST pts, respectively, and deletion of codon 557-558 in 16 pts. Two pediatric GISTs and one with NF-1 had no mutation in both genes. CDK activities were measurable in 63 (86%) pts, and median activities of CDK1 and CDK2 of GIST (19 U and 81) were not different from those of other tumors (18 and 47). In GIST, 20 recurrences and 6 deaths were observed. Size (p=0.0001), location (p=0.0007), mitosis (p=0.0044), rupture (p=0.0105), deletion of 557-558 (p=0.0037), CDK2 (p=0.0005) and CDK ratio (CDK2/CDK1) (p=0.0004) were significantly related to recurrence. In Cox regression analysis, only mitosis (p=0.0189) and CDK2 (p=0.0070) were significantly related with recurrence. In univariant analysis, CDK2 was correlated with size, mitosis, Ki-67, location, deletion of 557-558 and rupture, and, in multiple regression analysis, CDK2 was significantly related with mitosis (p=0.0384), and marginally with location (p=0.0806). Size, location, mitosis, rupture, deletion mutations, and activities of CDK1 and CDK2 were significant prognostic factors for cause-specific survival. Conclusions: Size, mitosis, location, deletion mutation of codon 557-558 and CDK2 activity are predictive for recurrence after R0 surgery of GIST. Genotyping and cell cycle analysis may be important in GIST risk stratification.

Final results of a University of Chicago phase II consortium trial of sorafenib (SOR) in patients (pts) with imatinib (IM)- and sunitinib (SU)-resistant (RES) gastrointestinal stromal tumors (GIST).

4 Background: GIST pts who develop resistance to IM and SU have few therapeutic options. SOR inhibits KIT, VEGFR, PDGFR-β, and BRAF kinases. In preclinical models, SOR has activity against several IM-RES mutations that are resistant to SU (Heinrich. ASCO 2009). Methods: We performed a multi-center, phase II trial of SOR in unresectable, KIT-expressing GIST pts who had disease progression on IM by RECIST. After FDA approval of SU for IM-RES GIST, the study was amended in 2/07 to require progression after both IM and SU. Pts received SOR 400 mg orally twice daily. CT scans were obtained Q2 28-day cycles. The primary endpoint was objective response rate. A Simon minimax 2-stage design required 1 response in 18 pts to proceed to a second stage, and 4 responses in 32 IM/SU RES pts for further investigation. Results: 38 pts (6 IM-RES, 32 IM/SU-RES) enrolled 1/06-9/09 at 6 centers. Median follow-up for survivors: 31 months (mo). Pt characteristics: male 55%; median age 57 (range 42-85); PS 0/1/2: 47%/47%/6%. Median cycles: 4 (range 1-37). 63% pts had at least 1 dose reduction. Partial response (PR): 13% (1 IM-RES, 4 IM/SU-RES); stable disease (SD): 55% (3 IM-RES, 18 IM/SU-RES). Disease control rate (PR + SD): 68%. Median progression-free survival: 5.2 mo (95% CI: 3.4, 7.4). Median overall survival 11.6 mo (95% CI: 8.8, 18.0); 1-year survival 50%; 2-year survival 29%. Three pts remain on trial receiving study drug (1 PR at 34 mo; 2 SD at 18 and 37 mo). Grade 3/4 toxicities (% pts): hand-foot syndrome 45%, hypertension 21%, diarrhea 8%, hypophosphatemia 8%, GI bleed 5%, rash 5%, thrombosis 3%, GI perforation 3%, fatigue 3%, anemia 3%. Conclusions: SOR is active in IM-and SU-resistant GIST. Some pts treated with SOR experience prolonged disease control. SOR is well-tolerated in GIST pts, but dose reductions are often required. SOR warrants further investigation in GIST. Supported by NCI grant N01-CM-62201. [Table: see text]

Phase II trial of nilotinib as third-line therapy for gastrointestinal stromal tumor (GIST) patients in Japan.

10015 Background: Patients with GIST resistant to both imatinib (IM) and sunitinib (SU) have a poor prognosis and few therapeutic options. The objective of this study is to investigate efficacy and safety of nilotinib as a third line therapy for Japanese GIST pts who have shown resistance and/or intolerance to imatinib and sunitinib. Methods: A single arm, open-label trial was conducted in 8 hospitals in Japan. The key eligibility criteria included histologically confirmed KIT-positive GIST and progression on or intolerance to both imatinib and sunitinib treatment. Pts were treated with nilotinib 400 mg b.i.d. The primary endpoint was disease control rate defined as rates of CR + PR + SD (lasting at least 24 weeks) assessed by central reviewers based on RECIST criteria. Registered with Clinical Trials.gov, number NCT00718562 and sponsored by Novartis Pharmaceuticals. Results: Among the 35 pts enrolled between Sep 2008 and Apr 2009, 26 (74.3%) were resistant to both IM and SU, 6 (17.1%) IM-resistant and SU-intolerant, 2 (5.7%) IM- intolerant and SU-resistant, and the remaining 1 (2.9%) intolerant to both. The median prior maximum doses were 400 mg (≥600 mg for 16/35 pts) for IM and 50 mg (50 mg for 34/35 pts) for SU. The median age was 57 years (range 26 - 76) and 22 (62.9%) pts were male. The most common primary sites of GIST were the small intestine (21 [60.0%] pts) and stomach (11 [31.4%] pts). The median exposure to nilotinib was 120 days (range 5-316) at the time of data cut-off (02Oct2009). Disease control rate at 24 weeks was 28.6% (90% CI ; [16.4%, 43.6%]). The median PFS was 113 days. The median OS was 310 days. The objective response rate was obtained for 2.9% with 1 PR pt who carried GIST with KIT mutations in exon 11 (dup 567 - 576) and exon 17 (D820G) after resistance to both imatinib and sunitinib, and 23 pts (65.7%) had SD as the best response. Nilotinib was well tolerated; the most common treatment-related AEs of any grade were nausea, vomiting, hyperbilirubinemia and appetite loss (28.6% each). No patients developed grade 3-4 hematological toxicities except for anemia (5.7%). Conclusions: These results suggest that nilotinib is effective in Japanese GIST pts who failed both imatinib and sunitinib and well tolerated. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Chugai Pharmaceutical, Novartis, Pfizer, sanofi-aventis Tsumura Co. Daiichi Sankyo, Kyowa Hakko Kirin, Novartis, Taiho Pharmaceutical, Wyeth, Yakult Honsha

Myelodysplastic syndromes developing after imatinib therapy for GIST

10532 Background: Imatinib mesylate 400 mg a day is the standard treatment for patients (pts.) who have advanced or metastatic gastrointestinal stromal tumor (GIST) even if different kit and PDGFRA mutations have a marked impact on the outcome of pts.; briefly, pts. with exon 9 mutations fared worse than those who had exon 11 mutations and both types of pts. did better than those with wild type genotype. Previously, we had detected clonal chromosomal abnormalities in the bone marrow of GIST pts. who developed a myelodysplastic syndrome during treatment with imatinib, so we performed a systematic study in a series of male and female GIST pts. during treatment with imatinib. Methods: Between January 2007 and December 2008, bone marrow samples for morphologic analysis, FISH and classical cytogenetics were obtained from 49 pts. (30 male; 19 female, mean age 62) with unresectable or metastatic GIST before and during treatment with 400 mg/d of imatinib. For pts. with progressive disease (15 pts.) or exon 9 mutant disease (5 pts.), imatinib 800 mg a day was scheduled. All pathologic material was reviewed to identify pts. with MDS or AML according to the WHO classification. Interphase and metaphase preparations were done according to the standard protocol. Results: At the time of analyses, all pts. were evaluable. Ten patients experienced anemia of grade 3–4 while five pts. developed granulocytopenia of grade 3–4. Eight pts. acquired cytogenetic chromosomal abnormalities in their bone marrow. A trisomy 8 was detectable in seven pts. even if, curiously, in four of these pts. this come and went on repeated sampling without any apparent clinical effect, three pts. developed an MDS (two refractory cytopenias with multilineage dysplasia, and one refractory cytopenia with multilineage dysplasia and ringed sideroblast). One patient developed a RAEB-1 with monosomy 7 which rapidly transformed into AML. Conclusions: During therapy with imatinib some pts. with GIST developed chromosomal abnormalities. Although, these occurrences are rare, the findings highlight the need for close monitoring of pts. with GIST treated with imatinib. No significant financial relationships to disclose.

Hypogonadism in male cancer patients treated with the tyrosine kinase inhibitors sunitinib (SUN) or sorafenib (SOR)

3565 Background: SUN and SOR are multi-targeted tyrosine kinase inhibitors (TKIs) inhibiting several kinases (VEGFR- 1,2; c-kit; PDGFR-α,β; flt-3; RET). SUN is approved for treatment of imatinib-resistant gastrointestinal stromal tumors (GIST) and metastatic renal cell carcinoma (RCC), SOR is used for RCC and hepatocellular carcinoma. We observed in some pts with fatigue under TKI treatment low testosterone (T) levels and started assessing the incidence and severity of gonadal dysfunction prospectively in male pts receiving these TKIs. Methods: Gonadal status (serum total testosterone (TT), free testosterone (FT), sex-hormone binding globulin (SHBG), luteinizing hormone (LH) and follicle-stimulating hormone (FSH) were evaluated in pts with RCC or GIST under SUN or SOR. SUN was given at a daily dose of 50 mg p.o. 4 weeks on, 2 weeks off, SOR at a daily oral dose of 800 mg. Results: We identified 27 pts (median age 63, range: 27–77), for which data on gonadal function were available, 23 RCC (85 %), 4 GIST (15%), with 22 (85.5%) receiving SUN and 5 (18.5%) SOR. Median treatment duration was 48 (2–202) weeks, 13 (48%) underwent dose reductions, in 4 (15%) pts due to grade 3 fatigue. All pts had at least once during TKI treatment T levels lower than normal (TT &lt; 300 ng/dL and/or FT &lt; 5 ng/dL), 17 (63%) had a low T with normal LH/FSH, 4 (15%) a low T with an elevated LH/FSH and 6 (22%) a low T and elevated FSH, but normal LH. The median TT level in the whole group was 194 ng/dL (21–477, normal range: 300–1,000 ng/dL), the median FT level in the whole group was 4.01 (0.45–9.07, normal range: 5–20 ng/dL). In the SUN cohort the median levels for TT and FT were slightly lower on day 28 in comparison to day 1 (184.5 vs 206 ng/dL for TT and 3.935 vs 4.225 ng/dl for FT). Pts with information available on testosterone at baseline (n = 8) tended to have slightly diminished baseline T levels (median: 222.5 [61–319] ng/dL), but 50% of these pts had been treated with other TKIs before. Two pts with grade 3 fatigue under SUN had very low T levels shortly after starting SUN (21 and 28 ng/dL, respectively). Conclusions: We observed a high incidence of hypogonadism in male RCC and GIST pts under treatment with SUN or SOR. Hypogonadism may likely contribute to the fatigue associated with these agents. [Table: see text]