Inflammatory myofibroblastic tumor (IMT) is a distinctive mesenchymal neoplasm characterized by a spindle-cell proliferation with an inflammatory infiltrate. Approximately half of IMTs carry rearrangements of the anaplastic lymphoma kinase (ALK) locus on chromosome 2p23, causing aberrant ALK expression. We report a sustained partial response to the ALK inhibitor crizotinib (PF-02341066, Pfizer) in a patient with ALK-translocated IMT, as compared with no observed activity in another patient without the ALK translocation. These results support the dependence of ALK-rearranged tumors on ALK-mediated signaling and suggest a therapeutic strategy for genomically identified patients with the aggressive form of this soft-tissue tumor. (Funded by Pfizer and others; ClinicalTrials.gov number, NCT00585195.).
Previous phase I/II trials indicate promising activity of lurbinectedin plus doxorubicin (DOX) in leiomyosarcoma (LMS). We describe here the rationale and design of SaLuDo, an open label, randomized, multicenter, seamless phase IIb/III study to evaluate the antitumor activity and safety of lurbinectedin plus DOX versus DOX alone in the first-line setting of metastatic LMS. The phase IIb stage will evaluate two schedules of the combination for the phase III stage given every 3 weeks (q3wk): DOX 50 mg/m2 plus lurbinectedin 2.2 mg/m2, and DOX 25 mg/m2 plus lurbinectedin 3.2 mg/m2. The control arm will be DOX 75 mg/m2 q3wk. The primary endpoint is progression-free survival by independent review; overall survival is the key secondary endpoint. Clinical trial registration: www.clinicaltrials.gov identifier is NCT06088290.
LBA10008 The full, final text of this abstract will be available at abstract.asco.org at 12:01 AM (EDT) on Monday, June 4, 2012, and in the Annual Meeting Proceedings online supplement to the June 20, 2012, issue of Journal of Clinical Oncology. Onsite at the Meeting, this abstract will be printed in the Monday edition of ASCO Daily News.
9547 Background: Sunitinib malate (previously known as SU11248) is an active therapy for GIST patients resistant to or intolerant of IM. During initial development, sunitinib was administered in 4–6 week cycles, with 2–4 weeks of drug dosing followed by 2 weeks off treatment. We previously reported suppression of tumor-related 18FDG avidity on PET imaging during sunitinib dosing, with rebound tumor uptake while off drug. This rebound, seen in 80% with initial PET suppression, did not correlate with lack of clinical benefit. We asked if this pattern persists in pts who benefited from long term (> 2 years) sunitinib therapy. Methods: Of 77 pts in our initial Phase I/II study, 7 remain on therapy with sunitinib for more than 2 years, 4 of whom had matched baseline PET and CT data to assess tumor metabolic activity on and off sunitinib dosing. PET scans were obtained at baseline, during initial treatment, during the off-treatment period, and again after > 2 years therapy. These 4 pts were followed for a median 39 months (range 35–45 months) and for a median of 35 cycles (range 27–47). Two achieved PR and two SD. Results: Initially, all 4 exhibited suppression of tumor FDG avidity with treatment followed by rebound during the off-treatment period. By 6 months, all showed complete suppression of FDG activity. After > 2 years on sunitinib, GIST lesions in 2 pts showed no activity on PET, even while off sunitinib, while GIST in 2 pts demonstrated rebound flare when off therapy. The GIST lesions have not progressed despite the transient metabolic rebound while off sunitinib. Conclusions: Metastatic lesions in pts with IM-resistant GIST benefiting from long-term sunitinib therapy display two patterns on PET imaging. GIST in certain pts who benefit from therapy demonstrates metabolic rebound of activity when off dosing, while lesions in other pts remain metabolically inert on PET even during the brief dosing breaks. Functional imaging may yield insights to differences in the underlying biology of GIST subtypes in different pts. [Table: see text]
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
