Circulating tumor DNA analysis of the phase III VOYAGER trial: KIT mutational landscape and outcomes in patients with advanced gastrointestinal stromal tumor treated with avapritinib or regorafenib

Abstract

Background: The current treatment paradigm of imatinib-resistant metastatic gastrointestinal stromal tumor (GIST) does not incorporate KIT/PDGFRA genotypes in therapeutic drug sequencing, except for PDGFRA exon 18-mutant GIST that is indicated for avapritinib treatment. Here, circulating tumor DNA (ctDNA) sequencing was used to analyze plasma samples prospectively collected in the phase III VOYAGER trial to understand how the KIT/PDGFRA mutational landscape contributes to tyrosine kinase inhibitor (TKI) resistance and to determine its clinical validity and utility.

Patients and methods: VOYAGER (N = 476) compared avapritinib with regorafenib in patients with KIT/PDGFRA-mutant GIST previously treated with imatinib and one or two additional TKIs (NCT03465722). KIT/PDGFRA ctDNA mutation profiling of plasma samples at baseline and end of treatment was assessed with 74-gene Guardant360® CDx. Molecular subgroups were determined and correlated with outcomes.

Results: A total of 386/476 patients with KIT/PDGFRA-mutant tumors underwent baseline (pre-trial treatment) ctDNA analysis; 196 received avapritinib and 190 received regorafenib. KIT and PDGFRA mutations were detected in 75.1% and 5.4%, respectively. KIT resistance mutations were found in the activation loop (A-loop; 80.4%) and ATP-binding pocket (ATP-BP; 40.8%); 23.4% had both. An average of 2.6 KIT mutations were detected per patient; 17.2% showed 4-14 different KIT resistance mutations. Of all pathogenic KIT variants, 28.0% were novel, including alterations in exons/codons previously unreported. PDGFRA mutations showed similar patterns. ctDNA-detected KIT ATP-BP mutations negatively prognosticated avapritinib activity, with a median progression-free survival (mPFS) of 1.9 versus 5.6 months for regorafenib. mPFS for regorafenib did not vary regardless of the presence or absence of ATP-BP/A-loop mutants and was greater than mPFS with avapritinib in this population. Secondary KIT ATP-BP pocket mutation variants, particularly V654A, were enriched upon disease progression with avapritinib.

Conclusions: ctDNA sequencing efficiently detects KIT/PDGFRA mutations and prognosticates outcomes in patients with TKI-resistant GIST treated with avapritinib. ctDNA analysis can be used to monitor disease progression and provide more personalized treatment.

Keywords: GIST; KIT; PDGFRA; avapritinib; ctDNA; regorafenib.

Figure 1.

Flow chart of ctDNA analyses performed and mutational findings.

Figure 2. KIT affected exons and codons.

The distribution of codons affected by any KIT variant was similar between treatment arms, which is better observed in those with higher frequency.

Figure 3.. KIT mutational heterogeneity.

Multiple KIT mutations were commonly detected among KIT-mutant tumors.

Figure 4.. KIT ATP-BP and A-loop mutations in ctDNA are prognostic of TKI activity in GIST.

Regorafenib had greater efficacy than avapritinib in patients with an ATP-BP mutation (A), a KIT A-loop mutation (B), and those with both ATP-BP and A-loop mutations (C). (D) Avapritinib improved PFS in the absence of a KIT mutation, while regorafenib was relatively unaffected. Ava, avapritinib; CI, confidence interval; mPFS, median progression-free survival; NE, not estimable; neg, negative; pos, positive; Reg, regorafenib.

Figure 5.. KIT/PDGFRA primary and secondary mutations determined in ctDNA in GIST are prognostic of TKI activity.

(A) KIT secondary mutations did not significantly affect the number of partial responses between treatments arms. Avapritinib efficacy was similar between primary KIT exon 9 and 11 mutations (B), whereas regorafenib trended to be more effective in patients with a primary exon 11 mutation (C). (D) Avapritinib had greater efficacy in patients with a primary PDGFRA exon 18 D842V mutation than regorafenib. CI, confidence interval; mPFS, median progression-free survival; NE, not estimable; PD, progressive disease; PR, partial response; SD, stable disease.

Figure 6.. Serial KIT ctDNA determinations detect resistance.

(A) KIT secondary mutation detection significantly increased upon disease progression. (B) Representative subclonal evolution showing increased allele frequency in subpopulations with a KIT exon 13 V654A mutation, in parallel to primary clonal KIT exon 11 mutations. ABP, ATP-BP; AL, activation loop; BL, baseline; EOT, end-of-treatment; FC, fold change; VAF, variable allele frequency.