Clonal evolution of resistance to imatinib (IM) in patients (pts) with gastrointestinal stromal tumor (GIST): molecular and radiologic evaluation of new lesions

Abstract

3010 Background: Resistance to IM is emerging as a clinical challenge in pts with metastatic GIST following durable benefit and response. Novel patterns of progression have been noted in GIST pts, and we have explored the molecular and radiologic patterns of IM-refractory disease to supplement existing conventional criteria. Methods: Pts with metastatic GIST treated with IM were followed with serial CT/MRI and 18FDG-PET scans. Where feasible, biopsies were performed to document disease progression. Results: 89 pts were followed for a median of 39 months (m). 42/89 pts eventually developed progressive disease (PD, SWOG criteria) following partial (n=34) or minor (n=8) response (25–49% bidimensional decrease). A unique “nodule within a mass” pattern was seen in 22/42 pts, thought to represent emergence of a clone resistant to IM. This was defined as a new enhancing nodular focus enclosed within a pre-existing, non- or hypo-enhancing tumor mass that previously responded to IM. Nodules arose prior to development of PD defined by “tumor size” criteria by median of 5m (range 0–13m) and were the first sign of progression in 17/22 pts. Development of nodules was independent of IM starting dose (400–800mg/d). 9 pts had IM dose increased, with no effect on nodule growth. 5 pts were treated with radiofrequency ablation and continuation of IM, with overall disease control for a further 4–12m. Comparative tumor biopsies were performed in 9 pts at baseline and with appearance of progressing nodules. Genotypic analyses of KITand PDGFRAkinases were performed, revealing new activating kinase mutations in 7/9 (78%) pts. Conclusions: The “nodule within a mass” is a unique pattern of disease progression seen in pts with GIST after an initial response to IM and reflects the emergence of IM-resistant clones, supported by the appearance of secondary mutations in tumor genotype. Conventional tumor measurements (SWOG/RECIST) do not adequately account for this subtle finding. A new enhancing nodule growing within a pre-existing tumor mass should be classified as a “new lesion” and should define at least partial progression of GIST. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis Novartis Novartis