Outcomes after cessation of therapy with alkylating agents (AA) for pancreatic neuroendocrine tumors (panNETs).

Abstract

394 Background: There are several therapies now available for panNETs, raising concern that treatment-related toxicity, namely myelosuppression, may preclude use of all treatments. AA are an effective therapy in panNETs, but can cause irreversible bone marrow suppression. For this reason, our institutional approach is to treat patients (pts) with AA for a defined time period of up to 12 months prior to a treatment holiday; anecdotally, we observed continued disease shrinkage or stability after drug cessation. We aimed to identify and characterize these exceptional responders (ER). Methods: We retrospectively identified pts with well differentiated panNETs treated at MSKCC with AA from 2007 to present, and identified those that were placed on a treatment holiday after response to therapy. Pts with continued disease response by radiographic report (tumor shrinkage or stable disease) for greater than 9 months while on a treatment holiday were considered exceptional responders (ER). Results: 124 patients were evaluable, with 104 pts (84%) receiving temozolomide and 18 pts (15%) receiving dacarbazine. 40 (32%), 57 (46%), and 22 (18%) pts had low, intermediate and high-grade tumors, respectively. 80 pts (65%) achieved a response to AA and 21 pts (17%) responded to therapy initially with subsequent disease progression. In total, 58 pts (47%) entered a treatment holiday; 39/58 pts (67%) were ER and 16/58 pts (28%) had disease growth in < 9 months. No significant differences in tumor grade ( P = 0.85) were seen between ER and those who had disease growth in < 9 months. Next generation sequencing results were available in 17 tumors of pts classified as ER; 14/17 (82%) with alterations in chromatin remodeling genes ( MEN1/DAXX/ATRX). Upon disease progression, 11 ER were reintroduced to alkylating agents; 9/11 (82%) had progressive disease or death after reintroduction of drug, and 2/11 (18%) responded and went on a second treatment holiday. Conclusions: We observed durable responses to AA after cessation of therapy. Many of the ER tumors harbored alterations in chromatin remodeling genes. Reintroduction of alkylating agents upon disease progression was generally ineffective.