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Jones RL , Serrano C , von Mehren M , George S , Heinrich MC , Kang YK , Schöffski P , Cassier PA , Mir O , Chawla SP , Eskens Falm , Rutkowski P , Tap WD , Zhou T , Roche M , Bauer S
Avapritinib in unresectable or metastatic PDGFRA D842V-mutant gastrointestinal stromal tumours: Long-term efficacy and safety data from the NAVIGATOR phase I trial
Eur J Cancer. 2021 Mar;145 :132-142
PMID: 33465704 URL: https://www.ncbi.nlm.nih.gov/pubmed/33465704
AbstractBACKGROUND: PDGFRA D842V mutations occur in 5-10% of gastrointestinal stromal tumours (GISTs), and previously approved tyrosine kinase inhibitors (TKIs) are inactive against this mutation. Consequently, patients have a poor prognosis. We present an updated analysis of avapritinib efficacy and long-term safety in this patient population. METHODS: NAVIGATOR (NCT02508532), a two-part, open-label, dose-escalation/dose-expansion phase I study, enrolled adult patients with unresectable GISTs. Patients with PDGFRA D842V-mutant GIST were a prespecified subgroup within the overall safety population, which included patients who received ≥1 avapritinib dose. Primary end-points were overall response rate (ORR) and avapritinib safety profile. Secondary end-points were clinical benefit rate (CBR), duration of response (DOR) and progression-free survival (PFS). Overall survival (OS) was an exploratory end-point. RESULTS: Between 7 October 2015 and 9 March 2020, 250 patients enrolled in the safety population; 56 patients were included in the PDGFRA D842V population, 11 were TKI-naïve. At data cut-off, median follow-up was 27.5 months. Safety profile was comparable between the overall safety and PDGFRA D842V populations. In the PDGFRA D842V population, the most frequent adverse events were nausea (38 [68%] patients) and diarrhoea (37 [66%]), and cognitive effects occurred in 32 (57%) patients. The ORR was 91% (51/56 patients). The CBR was 98% (55/56 patients). The median DOR was 27.6 months (95% confidence interval [CI]: 17.6-not reached [NR]); median PFS was 34.0 months (95% CI: 22.9-NR). Median OS was not reached. CONCLUSION: Targeting PDGFRA D842V-mutant GIST with avapritinib resulted in an unprecedented, durable clinical benefit, with a manageable safety profile. Avapritinib should be considered as first-line therapy for these patients.
Notes1879-0852 Jones, Robin L Serrano, César von Mehren, Margaret George, Suzanne Heinrich, Michael C Kang, Yoon-Koo Schöffski, Patrick Cassier, Philippe A Mir, Olivier Chawla, Sant P Eskens, Ferry A L M Rutkowski, Piotr Tap, William D Zhou, Teresa Roche, Maria Bauer, Sebastian Journal Article England Eur J Cancer. 2021 Jan 15;145:132-142. doi: 10.1016/j.ejca.2020.12.008.