# Outcomes of Late-Line Systemic Treatment in GIST: Does Sequence Matter?

## TL;DR

This study finds that the order of using ripretinib and avapritinib in treating advanced gastrointestinal stromal tumors does not affect treatment outcomes.

## Contribution

The study provides evidence that the efficacy of ripretinib and avapritinib in late-line GIST treatment is not influenced by the sequence of administration.

## Key findings

- Response rates and time-to-progression were similar regardless of drug sequence.
- Overall survival was comparable between patients treated with ripretinib followed by avapritinib and vice versa.
- No significant difference in efficacy was observed based on the order of drug administration.

## Abstract

Ripretinib, with reported broad activity against KIT-mutated gastrointestinal stomal tumors (GISTs), has been approved in the fourth-line setting, while avapritinib, which has robust activity against PDGFRA D842V and KIT activation loop (AL) mutations, has been approved for tumors with PDGFRA exon 18 mutations in any line of treatment. Avapritinib has fair activity against tumors with KIT exon 17 AL mutations or primary exon 9 mutations, as reported in the NAVIGATOR trial. That finding led to the National Comprehensive Cancer Network guidelines’ inclusion of avapritinib as an available option after progression of disease on other FDA-approved tyrosine kinase inhibitors. As ripretinib and avapritinib have shown overlapping activity against KIT secondary mutations, we investigated whether the benefit of trying one of these drugs remains after exposure to the other. This study reports no significant difference in efficacy of these drugs regarding the sequence in which they were administered to the patient.

Ripretinib and avapritinib have demonstrated activity in the late-line treatment of gastrointestinal stomal tumors (GISTs). We investigated whether patients previously treated with ripretinib benefit from avapritinib, and vice versa. Patients diagnosed with metastatic/unresectable GIST and treated with both drugs at two institutions in 2000–2021 were included. Patients were grouped by drug sequence: ripretinib–avapritinib (RA) or avapritinib–ripretinib (AR). Radiographic response was evaluated using RECIST 1.1. Kaplan–Meier and log-rank tests were used to compare time-to-progression (TTP) and overall survival (OS). Thirty-four patients (17 per group) were identified, with a median age of 48 years. The most common primary site was the small bowel (17/34, 50%), followed by the stomach (10/34, 29.4%). Baseline characteristics and tumor mutations were not significantly different between groups. Response rates (RRs) for ripretinib were 18% for RA and 12% for AR; RRs for avapritinib were 12% for AR and 18% for RA. Median TTPs for ripretinib were 3.65 months (95%CI 2–5.95) for RA and 4.73 months (1.87–15.84) for AR. Median TTPs for avapritinib were 5.39 months (2.86–18.99) for AR and 4.11 months (1.91–11.4) for RA. Median OS rates following RA or AR initiation were 29.63 (95%CI 13.8–50.53) and 33.7 (20.03–50.57) months, respectively. Both ripretinib and avapritinib were efficacious in the late-line treatment of GIST, with no evidence that efficacy depended on sequencing.