Discussion
SDH-deficient GIST, tumor, GIST, SDH-deficient, imatinib-resistant GIST
DISEASE, GIST, TUMOR
In this phase II trial, we found that 86.7% of 15 patients treated with regorafenib, mainly as upfront therapy of advanced disease, had DCR at 12 weeks, while 13% and 54% had partial response according to RECIST and Choi criteria respectively and according to central radiology review. Moreover, the 20% decrease in median tumor density, and the fact that 60% of patients experienced some tumor shrinkage suggest activity of regorafenib in KP-wGIST, even when the study was prematurely closed.The activity of imatinib reported in the context of KP-wGIST has fluctuated from 23% in the pre-NGS era [When we consider the 9 SDH-deficient patients in our series, 2 (22%) RECIST partial responses and 7 (78%) cases of stable disease were centrally detected. All of them were gastric and almost universally expressed positive-KIT and DOG1-positive immunostaining. In line with our findings, regorafenib achieved a median PFS of 42.9 months in a retrospective series of SDH-deficient and likely SDH-deficient GIST. In the same study, authors reported a median PFS of 14.7 and 18 months for imatinib and sunitinib respectively [Sunitinib induced no responses and provided a clinical benefit rate of 56% in 9 patients classified as KP-wGIST. The trial explored sunitinib in phase I/II with imatinib-resistant GIST patients [The fact that 47% of supposed KP-wGIST by Sanger were really Another limitation of the study was the low compliance regarding quality-of-life questionnaires, probably related to the academic nature of the study, due to budget constraints limiting on-site monitoring. The almost universal temporal discontinuations (93%) indicated that the treatment is toxic and required reduction adjustments in almost half of the patients (53%). This was in line with the accumulated experience with regorafenib in the third line of advanced GIST patients, where it is difficult to maintain the dose of 160 mg per day.In conclusion, KP-wGIST represents an uncommon subset within GIST patients, rarer than initially expected using Sanger sequencing. Within this heterogeneous population, regorafenib activity compares favorably with other tyrosine kinase inhibitors especially in the SDH-deficient GIST subset, and consequently it should be taken into consideration as upfront therapy of advanced KP-wGIST patients.