Avapritinib did not improve progression-free survival (PFS) when compared with regorafenib as third-line or later treatment in patients with unresectable or metastatic gastrointestinal stromal tumors (GIST), according to phase 3 trial results published in the Journal of Clinical Oncology.

Although the primary endpoint of PFS was not met, a small subgroup of patients with PDGFRA D842V-mutant GIST had a 100% disease control rate with avapritinib.

Avapritinib, which selectively inhibits KIT– and PDGFRA-mutant kinases, demonstrated activity against PDGFRA D842V-mutant and later-line KIT-mutant GIST in the phase 1 NAVIGATOR study (ClinicalTrials.gov Identifier: NCT02508532).2, 3

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The results of NAVIGATOR led to the initiation of the phase 3 VOYAGER trial (ClinicalTrials.gov Identifier: NCT03465722), which was designed to compare avapritinib with regorafenib.

VOYAGER enrolled 476 patients with unresectable or metastatic GIST previously treated with imatinib and 1-2 other TKIs. The patients were randomly assigned to receive avapritinib (240 patients) or regorafenib (236 patients).

The median PFS was 4.2 months in the avapritinib arm and 5.6 months in the regorafenib arm, which was not significantly different (hazard ratio [HR], 1.25; 95% CI, 0.99-1.57; P =.055).

Likewise, there was no significant difference in median PFS between subgroups of patients treated with avapritinib or regorafenib as third-line treatment (HR, 1.26; 95% CI, 0.98-1.61; P =.068) or fourth-line treatment (HR, 1.19; 95% CI, 0.66-2.15; P =.550).

The overall survival (OS) data were not mature with a median follow-up of 8.5 months for the avapritinib arm and 9.6 months for the regorafenib arm. The 12-month OS estimates were 68.2% for the avapritinib arm and 67.4% for the regorafenib arm.

The objective response rate (ORR) was significantly higher with avapritinib than with regorafenib — 17.1% and 7.2%, respectively (P <.001).

However, the median duration of response was shorter with avapritinib than with regorafenib — 7.6 months and 9.4 months, respectively. The disease control rate (DCR) was 41.7% and 46.2%, respectively.

Among 7 patients with PDGFRA D842V-mutant GIST who received avapritinib, the ORR was 42.9%, and the DCR was 100%. Among the 6 patients with PDGFRA D842V-mutant GIST who received regorafenib, the ORR was 0%, and the DCR was 33.3%.

The rate of treatment-related adverse events (TRAEs) was 92.5% in the avapritinib arm and 96.2% in the regorafenib arm. The rate of grade 3 or higher TRAEs was 55.2% and 57.7%, respectively.

The most common any-grade TRAEs in the avapritinib arm were anemia (40.2%), nausea (39.3%), and fatigue (35.1%). The most common any-grade TRAEs in the regorafenib arm were fatigue (34.2%), diarrhea (34.6%), and palmar-plantar erythrodysesthesia syndrome (59.0%).

“As no PFS benefit was observed with avapritinib over regorafenib (intention-to-treat population), our findings do not suggest any change in later-line treatment paradigms for KIT-mutant GIST,” the study authors wrote. “However, avapritinib remains the most active available agent for patients with [PDGFRA] D842V-mutant GIST.”

Disclosures: This research was supported by Blueprint Medicines Corporation. Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of disclosures.

Reference

  1. Kang YK, George S, Jones RL, et al. Avapritinib versus regorafenib in locally advanced unresectable or metastatic GI stromal tumor: A randomized, open-label phase III study. J Clin Oncol. Published online August 03, 2021. doi: 10.1200/JCO.21.00217
  2. Heinrich MC, Jones RL, von Mehren M, et al. Avapritinib in advanced PDGFRA D842V-mutant gastrointestinal stromal tumour (NAVIGATOR): A multicentre, open-label, phase 1 trial. Lancet Oncol. 2020; 21(7):935-946. doi:10.1016/S1470-2045(20)30269-2
  3. George S, Jones RL, Bauer S, et al. Avapritinib in patients with advanced gastrointestinal stromal tumors following at least three prior lines of therapy. Oncologist. 2021;26(4):e639-e649. doi:10.1002/onco.13674

Topics:

Gastrointestinal Cancer Sarcoma