(P 108) NILOTINIB REVISITED: SALVAGE USE IN PATIENTS WITH SEVERE IMATINIB-TOXICITY

Objective: Imatinib is the standard first-line therapy for metastatic GIST and displays the most favorable toxicity profile of all approved drugs in GIST. In rare cases, severe imatinib toxicity may require permanent discontinuation in the absence of resistance. A switch to other approved drugs may lead to unwanted side effects such as hand-foot-syndrome, mucositis, hypertension or alopecia, which can be particularly long-lasting in a non-resistant disease setting. Nilotinib is a potent inhibitor of KIT exon 11 but not exon 9 mutant GIST and little is known about cross-toxicity in patients with severe imatinib side effects.

Methods: Patients were identified from our institutional GIST database that were treated with nilotinib as salvage treatment following severe imatinib toxicity. Clinical data and laboratory values were extracted from the electronic hospital information system and adverse events were graded according to CTCAE5.0 criteria. We further re-evaluated nilotinib activity against a broad range of KIT and PDGFRA mutant isogenic GIST cell lines with various secondary resistance mutations using SRB cell proliferation assay.

Results: Of 406 patients treated with imatinib, 23 had to stop treatment due to toxicity. Of those, four patients with °IV liver or °II-III skin toxicity (eczema, hand-foot-syndrome) were switched to nilotinib 800mg qd upon improvement of toxicity to at least °I. Notably, none of these patients showed cross-toxicities except one patient having an II° ALT increase 5 weeks after nilotinib start, decreasing to I° after 20d treatment pause without recurrence after restart. Only one patient with imatinib liver toxicity developed I° eczema. No additional clinically relevant side effects were observed. Patients had disease control for 11+, 15+, 36, and 59 months. One patient developed a single hepatic metastasis which harbored a secondary point mutation in KIT exon 9 (S476I). Using CRISPR/Cas9 technology we modeled this mutation in a GIST-T1 cell line which recapitulated resistance in vitro. We further screened nilotinib in a panel of GIST cell lines harboring primary exon 9 and exon 11 as well as a broad range of secondary KIT mutations. Nilotinib exhibited a more than 10-fold higher GR50 in exon 9 vs. exon 11 primary mutant GIST, mirroring the findings from the phase III trial. Notably, the inhibitory profile of nilotinib shows, similar to imatinib, high potency only in exon 11 mutant GIST that lack secondary mutations. Interestingly, unlike in T315I-BCR-ABL mutant cells, nilotinib shows no activity in GIST cells harboring the secondary gate-keeper mutation KIT-T670I.

Conclusion: Despite the small-sized cohort, our data suggests that for patients with severe imatinib-toxicity, nilotinib may represent a well-tolerated alternative – particularly in the context of its imminent patent expiration. We show for the first time a secondary mutation in exon 9 as mechanism of resistance to a highly specific KIT inhibitor that lacks activity against primary exon 9 mutations. Additional analyses are currently being performed to gain insight into the properties of nilotinib and imatinib to support the observations from clinical and in vitro settings.