(P 166) D842V - A TALE OF TWO STAGES: COMPARATIVE ANALYSIS OF OVERALL SURVIVAL AND TREATMENT RESPONSE IN GIST PATIENTS WITH PDGFRA D842V MUTATIONS

Objective: Gastrointestinal Stromal Tumors (GIST) are characterized by diverse molecular subtypes, with KIT and PDGFRA being predominant. These mutations influence the prognosis and treatment response. PDGFRA D842V (D842V) mutations are characterized by their heterogeneous and often indolent behavior. This study aims to compare the overall survival (OS) and treatment responses between patients with D842V mutations and those with KIT exon 11 mutations, highlighting the impact of recent advancements in targeted therapies.

Methods: A retrospective analysis using data from the LRG Patient Registry focused on patients with D842V mutations compared to those with KIT exon 11 mutations. Key outcomes measured included OS and recurrence free survival (RFS) from diagnosis, progression free survival (PFS) and OS in first-line advanced settings. We excluded patients diagnosed prior to 2000 from RFS and OS from diagnosis analyses to reduce survivors’ bias.

Results: When all stages of disease were considered, KIT exon 11 (n = 941) and PDGFRA exon 18 D842V (n = 62) mutations have similar overall survival (OS) from diagnosis (17.2 years and 20.3 years respectively, p = 0.60, figure 1A) This long survival is, however, achieved in very different ways.
Patients with D842V mutations have much longer recurrence-free survival (RFS) than patients with KIT exon 11 mutations, (median not reached and 6.3 years respectively, HR 0.33, p = 0.001) and a lower percentage of patients with metastatic disease at the time of diagnosis (n = 9, 14.5% and n = 280, 29.8% respectively, p = 0.008). However, the D842V patients with metastatic disease have historically had less treatment options and have a lower OS (median 6.4 years) compared to KIT exon 11 patients (n = 280, median OS 11.7 years, p = 0.003, figure 1B).
For patients with a single tumor at diagnosis, adjuvant imatinib improves both RFS and OS for KIT exon 11 patients, but not for D842V patients (data not shown).
To assess the efficacy of treatments for D842V, we analyzed first-line treatment for advanced disease compared to KIT exon 11 (table 1, figure 2A). We then combined all lines of treatment (1L – 4L) and limited the analysis to four medications (table 2). In this analysis, the median PFS for avapritinib was 28.8 months, strongly suggesting that OS for metastatic D842V patients will improve with more common avapritinib usage.
For metastatic disease, D842V patients have shorter OS than KIT exon 11 patients regardless of whether OS is calculated from diagnosis (n = 9, median OS 6.4 years and n=280, OS 11.7 years respectively, HR 3.26, p = 0.003, figure 2B) or from the start of first-line treatment for advanced/metastatic GIST, figure 2 (n = 17, median OS 5.8 years and n=547, OS 12.1 years respectively, HR 2.80, p = 0.003, figure 2C).

Conclusion: Although both mutation groups exhibit comparable overall survival, the underlying mechanisms differ significantly.
For patients with a single tumor at diagnosis, those with D842V mutations generally exhibit a more indolent course initially with longer RFS. For KIT exon 11 patients, adjuvant imatinib significantly increases RFS and OS in high-risk patients, making the entire KIT exon 11 cohort (low/intermediate/high-risk) more comparable to D842V patients.
For patients with metastatic disease, KIT exon 11 patients have more treatment options as well as a longer history of effective treatments. This has resulted in a longer OS for KIT exon 11 in the metastatic setting, however, this gap is likely to narrow with the 2020 approval of avapritinib for D842V patients. We also have noted that there appears to be significant interpatient variability within the D842V metastatic setting, with some patients exhibiting a more indolent disease course even prior to the introduction of avapritinib.
There is a critical need to develop additional novel therapies specifically targeting patients with the D842V mutation.