ctDNA sequencing can efficiently detect KIT/PDGFRA mutations and predict outcomes in patients with tyrosine kinase inhibitor-resistant gastrointestinal stromal tumor treated with avapritinib.
ctDNA analysis helps monitor disease progression and personalize treatment for patients with gastrointestinal stromal tumor (GIST) as it can efficiently detect KIT/PDGFRA mutations and prognosticate outcomes in patients who are tyrosine kinase inhibitor (TKI)-resistant and treated with avapritinib (Ayvakit).1
Findings come from the phase 3 VOYAGER study (NCT03465722) which revealed that ctDNA-detected KIT ATP-binding pocket (ATP-BP) mutations negatively prognosticate avapritinib activity, making for a median progression-free survival (mPFS) of 1.9 vs 5.6 months for regorafenib (Stivarga).
For regorafenib, the mPFS remains consistent, regardless of the activation loop (A-loop) and ATP-BP mutations and was greater than mPFS with avapritinib in this population.
“There's emerging data from some prospective clinical trials from our retrospective series and laboratory data that KIT exon 13-mutated resistance GIST is most sensitive to sunitinib and relatively resistant to other TKIs. On the other hand, KIT exon 17-mutated resistant GIST seems to be much more sensitive to other TKIs, such as ripretinib and regorafenib than sunitinib. That's laying the groundwork of the possibility that perhaps we should be performing circulating tumor DNA and all of our resistant patients and treating them with the optimal therapy that gives them the best chance of response,” Jonathan C. Trent, MD, PhD, professor and associate director for Clinical Research at Sylvester Comprehensive Cancer Center, University of Miami Health System, Miami, Florida, told Targeted OncologyTM, in an interview.
The open-label, randomized, multicenter, phase 3 VOYAGER study enrolled a total of 476 with KIT/PDGFRA-mutant GIST who were previously treated with imatinib (Gleevec) and 1-2 TKIs. Patients were treated with either oral avapritinib 300 mg every day in continuous 28-day treatment cycles (n = 240) or regorafenib 160 mg daily for 21 days every 28 days, in a 3-weeks-on, 1-week-off fashion (n = 236).2
A total of 386 patients of the 476 with KIT/PDGFRA-mutant tumors underwent baseline ctDNA analysis with 196 receiving avapritinib and 190 receiving regorafenib.1 ctDNA was detected in 168 and 190 patients, respectively. Between treatment arms, KIT and PDGFRA mutations were detected in 75.1% and 5.4%, respectively. KIT resistance mutations were found in the A-loop (80.4%) and ATP-BP (40.8%), while 23.4% of patients had both. Among patients, an average of 2.6 KIT mutations were detected.
Data revealed that the determination of ctDNA among these patients with GIST in the third- or fourth-line setting following disease progression on imatinib and sunitinib (Suntent) allowed identification of 50 novel pathogenic KIT variants. This made up 28.0% of the total identified. Half of these variants were deletions, insertions, or indels affecting KIT exon 11, however, 14 KIT variants were missense substitutions affecting a wide range of exons.
The baseline ctDNA analysis from the VOYAGER trial also showed there to be a shift in resistance patterns after 2-3 lines of treatment with secondary KIT ATP-BP pocket mutation variants, particularly V654A, being enriched upon disease progression with avapritinib.
Notably, there was an arguably low level of complex heterogeneity as 82% of the patients displayed only 1-3 KIT variants. A greater spectrum of KIT pathogenic variants vs previous studies, including exons and codons previously not known to be affected, was also found in this ctDNA analysis. Additionally, these findings show that ctDNA assessment might predict TKI activity in patients with metastatic GIST in the third- and fourth-line setting.
Overall, ctDNA sequencing can reliably detect KIT/PDGFRA mutations and is linked with outcomes in patients with metastatic, TKI-resistant GIST who are treated with avapritinib. The continued exploration of ctDNA analysis to monitor disease progression and provide more personalized treatment for this patient population is warranted.