Gastrointestinal Stromal Tumors Lesions Research Articles

Safety and efficacy of percutaneous radio-frequency ablation (RFA) in patients (pts) with metastatic gastrointestinal stromal tumor (GIST) with clonal evolution of lesions refractory to imatinib mesylate (IM)

9024 Background: IM is a highly effective treatment for metastatic/unresectable GIST. Although pts may exhibit durable systemic disease control, with time clonal evolution of lesions refractory to IM emerge and require alternative treatment approaches. We have evaluated the role of percutaneous RFA in this subset of pts with single or oligoclonal progressing GIST lesions who are in good performance status. Methods: Pts with limited sites of GIST progressing despite continuation of IM were treated with CT-guided RFA. All pts had staging with CT/MRI as well as functional imaging with 18FDG PET scans, both before and after RFA. Biopsy of the target lesions was performed before RFA. Results: Nine pts treated with imatinib for a median of 25 months (m) (range 18–36 m) underwent RFA for single or limited site(s) of progressing disease. Sites of progression: 8/9 pts with liver metastases, 1/9 with soft tissue disease. 5/9 of these pts developed a new nodule within a pre-existing GIST lesion, the remaining 4/9 ha...

Combination signal transduction inhibition: a phase I/II trial of the oral mTOR-inhibitor everolimus (E, RAD001) and imatinib mesylate (IM) in patients (pts) with gastrointestinal stromal tumor (GIST) refractory to IM

3002 Background: Primary resistance to IM in advanced GIST pts occurs rarely (<15%), but eventually pts may develop secondary resistance, possibly due to other mutations of KIT, genomic amplification of KIT, as well as activation of alternative oncogenic signaling mechanisms. Signal-profiling studies of GIST lesions with initial response to IM and subsequent clonal evolution of IM-resistant disease demonstrate close association between KIT and AKT/mTOR activity. Synergism has been shown in-vitro between IM and E, slowing proliferation and inducing apoptosis in primary GIST cell lines resistant to IM. Methods: We have initiated a phase I/II clinical study to test feasibility of the combination of E + IM, and also to assess the effect of E+IM in combination in GIST pts refractory to IM. Pts with metastatic GIST are eligible if progressing after ≥4 months' IM therapy at optimal doses, including at least 2 months at ≥600mg/d. Initially, PK interaction was assessed by measuring drug levels of IM alone (600mg/d), then E alone (20mg once weekly), and then of the combination. Serial assessments include FDG-PET and CT or MRI. Tumor biopsies are performed before and on therapy to evaluate changes in intratumoral signaling. Results: In 12 patients evaluated for PK interaction, IM increased levels of E (mean AUC by 3.7 fold, Cmax by 2.2 fold) but E did not effect levels of IM or its main metabolite. Tolerability was good overall. PET demonstrated dramatically increased tumoral FDG-avidity on interruption of IM, and then reduced FDG-avidity with the combination. One patient maintains objectively stable disease after 10 months on study. Conclusions: The increase in E bioavailability could be via competition with IM for CYP3A4 and/or P-glycoprotein. The initial increase in tumor FDG uptake on PET demonstrates residual suppression of GIST clones by IM and their reactivation upon IM interruption. To achieve more consistent exposure to E, this study is ongoing with subsequent intercohort dose escalation testing daily E (2.5–10mg/d) with 600mg/d IM. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis Novartis Novartis Novartis Novartis; Amgen; Aventis; Roche; Schering-Plough; PharmaMar; Pfizer

SU11248, a multi-targeted tyrosine kinase inhibitor, can overcome imatinib (IM) resistance caused by diverse genomic mechanisms in patients (pts) with metastatic gastrointestinal stromal tumor (GIST)

3001 Background: Resistance to Imatinib mesylate (IM) following initial tumor regression and disease control in GIST is increasingly recognized as an unmet medical need. IM resistance can be correlated with the appearance of secondary mutations in the KIT or PDGFRA tyrosine kinases in GIST lesions refractory to IM; activation of alternative signaling pathways and different structural biology of the new mutant kinases contribute to emergence of IM-resistant GIST clones. Methods: Phase I/II clinical trial of SU11248 in pts with progressing IM-resistant GIST. Tumor biopsies were obtained to define the mutational status of the KIT and PDGFRA kinases by dHPLC and sequencing assays. Results: 98 pts with progressive GIST have been enrolled in this ongoing study; with tumor response data available in 48 pts and GIST genotype determined in 41. The phase II regimen chosen was SU11248 50 mg orally once daily for 4 weeks, followed by a 2 week period off drug in each 6 wk cycle. SU11248 therapy induced clinical benefit (defined by objective response or stable disease for ≥ 6 months) in 26/48 (54%) of these previously progressing pts, with 6/48 (13%) confirmed partial responses (PR). KIT exon 9 mutants had fewer secondary mutations than Exon 11 GIST. Conclusions: SU11248 therapy can induce objective responses and control progressive disease in pts with several mutational variants of GIST with different genomic mechanisms of resistance to IM. These data are the basis for a phase III trial to define further the activity of SU11248 in pts with IM-resistant GIST. Understanding the efficacy of SU11248 in IM-resistant GIST should help to elucidate the structural biology of PDGFRA, KIT and other aberrant signaling pathways in the pathogenesis of GIST and may have relevance to molecularly targeted therapies for other malignancies. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Pfizer Novartis; Pfizer Pfizer Novartis; Pfizer Pfizer Oncology

SU11248, a multi-targeted tyrosine kinase inhibitor, can overcome imatinib (IM) resistance caused by diverse genomic mechanisms in patients (pts) with metastatic gastrointestinal stromal tumor (GIST)

3001 Background: Resistance to Imatinib mesylate (IM) following initial tumor regression and disease control in GIST is increasingly recognized as an unmet medical need. IM resistance can be correlated with the appearance of secondary mutations in the KIT or PDGFRA tyrosine kinases in GIST lesions refractory to IM; activation of alternative signaling pathways and different structural biology of the new mutant kinases contribute to emergence of IM-resistant GIST clones. Methods: Phase I/II clinical trial of SU11248 in pts with progressing IM-resistant GIST. Tumor biopsies were obtained to define the mutational status of the KIT and PDGFRA kinases by dHPLC and sequencing assays. Results: 98 pts with progressive GIST have been enrolled in this ongoing study; with tumor response data available in 48 pts and GIST genotype determined in 41. The phase II regimen chosen was SU11248 50 mg orally once daily for 4 weeks, followed by a 2 week period off drug in each 6 wk cycle. SU11248 therapy induced clinical benefit (defined by objective response or stable disease for ≥ 6 months) in 26/48 (54%) of these previously progressing pts, with 6/48 (13%) confirmed partial responses (PR). KIT exon 9 mutants had fewer secondary mutations than Exon 11 GIST. Conclusions: SU11248 therapy can induce objective responses and control progressive disease in pts with several mutational variants of GIST with different genomic mechanisms of resistance to IM. These data are the basis for a phase III trial to define further the activity of SU11248 in pts with IM-resistant GIST. Understanding the efficacy of SU11248 in IM-resistant GIST should help to elucidate the structural biology of PDGFRA, KIT and other aberrant signaling pathways in the pathogenesis of GIST and may have relevance to molecularly targeted therapies for other malignancies. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Pfizer Novartis; Pfizer Pfizer Novartis; Pfizer Pfizer Oncology

Combination signal transduction inhibition: a phase I/II trial of the oral mTOR-inhibitor everolimus (E, RAD001) and imatinib mesylate (IM) in patients (pts) with gastrointestinal stromal tumor (GIST) refractory to IM

3002 Background: Primary resistance to IM in advanced GIST pts occurs rarely (<15%), but eventually pts may develop secondary resistance, possibly due to other mutations of KIT, genomic amplification of KIT, as well as activation of alternative oncogenic signaling mechanisms. Signal-profiling studies of GIST lesions with initial response to IM and subsequent clonal evolution of IM-resistant disease demonstrate close association between KIT and AKT/mTOR activity. Synergism has been shown in-vitro between IM and E, slowing proliferation and inducing apoptosis in primary GIST cell lines resistant to IM. Methods: We have initiated a phase I/II clinical study to test feasibility of the combination of E + IM, and also to assess the effect of E+IM in combination in GIST pts refractory to IM. Pts with metastatic GIST are eligible if progressing after ≥4 months' IM therapy at optimal doses, including at least 2 months at ≥600mg/d. Initially, PK interaction was assessed by measuring drug levels of IM alone (600mg/d), then E alone (20mg once weekly), and then of the combination. Serial assessments include FDG-PET and CT or MRI. Tumor biopsies are performed before and on therapy to evaluate changes in intratumoral signaling. Results: In 12 patients evaluated for PK interaction, IM increased levels of E (mean AUC by 3.7 fold, Cmax by 2.2 fold) but E did not effect levels of IM or its main metabolite. Tolerability was good overall. PET demonstrated dramatically increased tumoral FDG-avidity on interruption of IM, and then reduced FDG-avidity with the combination. One patient maintains objectively stable disease after 10 months on study. Conclusions: The increase in E bioavailability could be via competition with IM for CYP3A4 and/or P-glycoprotein. The initial increase in tumor FDG uptake on PET demonstrates residual suppression of GIST clones by IM and their reactivation upon IM interruption. To achieve more consistent exposure to E, this study is ongoing with subsequent intercohort dose escalation testing daily E (2.5–10mg/d) with 600mg/d IM. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis Novartis Novartis Novartis Novartis; Amgen; Aventis; Roche; Schering-Plough; PharmaMar; Pfizer