More Benefit Observed With Avapritinib Than Other TKIs in Mutated GIST

Dylann Cohn-Emery

A retrospective analysis showed there were more durable survival outcomes with avapritinib (Ayvakit) versus other tyrosine kinase inhibitors (TKIs) in adult patients with gastrointestinal stromal tumors (GIST) and a platelet-derived growth factor receptor A (PDGFRA) D842V mutation, according to the published data in BMC Cancer.1

“Our data demonstrated that there is truly a clinically meaningful benefit to this drug compared with the benefit derived from other drugs, even among what is likely a group of patients with potentially more severe disease,” Margaret von Mehren, MD, the lead investigator of the trial, said in a statement.2

Avapritinib is a potent inhibitor of KIT and PDGFRA tyrosine kinases and the first therapy approved for patients with GIST and a PDGFRA exon 18 mutation.3 The data for this drug was from a dose escalation and dose expansion study, the phase 1 multicenter, open-label, single-arm NAVIGATOR trial (NCT02508532). The investigators looked at oral avapritinib at 400 mg, and subsequently 300 mg, daily for 28-day cycles in patients with advanced GIST.4

For this indirect, retrospective analysis, NAVIGATOR was compared with Study 1002 in patients who had unresectable or metastatic GIST and a PDGFRA D842V mutation receiving another first-line TKI.1 The patients were evaluated for the primary end point of overall survival (OS) from the start of their reference treatment. von Mehren et al looked at 56 patients from the NAVIGATOR study and 19 patients from Study 1002. These patients were also observed for progression-free survival (PFS) as a secondary end point.

“We are never going to be able to do a randomized trial in patients with this specific mutation because it occurs in such a small number of patients and because information suggests that these other drugs do not work,” von Mehren, chief of the Division of Sarcoma Medical Oncology and professor in the Department of Hematology/Oncology at Fox Chase Cancer Center, said in the press release.2 “This study was another way to provide context to the outcomes we are seeing with avapritinib.”

After inverse probably of treatment weighting-adjusted Kaplan-Meier analysis of OS, the median was not reached for patients on the NAVIGATOR trial treated with either avapritinib doses versus 12.6 months for those on Study 1002.1 There was a 100% OS rate at 6 months for patients on avapritinib compared with 56% for patients on other TKIS. At 48 months, the OS rates were 63% and 17%, respectively (P = .0001).

In a separately analyzed subgroup of 38 patients treated with the recommended phase 2 dose of 300 mg or the maximum tolerated dose of 400 mg of avapritinib, there was an adjusted OS rate of 100% at 6 months for avapritinib versus 68% in the Study 1002 trial. The 36-month OS rate was 73% in patients receiving avapritinib and 20% for patients receiving other TKIs (P = .0016).

Patients in the NAVIGATOR trial had an adjusted median PFS of 29.5 months compared with 3.4 months for patients in the Study 1002 trial. All patient characteristics were adjusted by propensity score for imbalances among the 2 study groups.

In the original data published for NAVIGATOR, the overall response rate was 88%, and the complete and partial response rates were 9% and 79%, respectively (n = 56).4 Thirteen percent of patients had stable disease and none had progressive disease.

“Until the FDA approval of avapritinib,3 we did not have a drug that was effective against this mutation,” von Mehren said in a statement.2 “If these patients had their disease return, we had no real therapeutic options apart from attempting surgery or enrolling in a clinical trial.”

PDGFRA mutations are seen in about 10% to 15% of patients with GIST, and D842V is the most common mutations, according to von Mehren.

References:

1. von Mehren M, Heinrich MC, Shi H, et al. Clinical efficacy comparison of avapritinib with other tyrosine kinase inhibitors in gastrointestinal stromal tumors with PDGFRA D842V mutation: a retrospective analysis of clinical trial and real-world data. BMC Cancer. 2021;21(1):291. doi:10.1186/s12885-021-08013-1

2. Avapritinib provided greater benefit than other tyrosine kinase inhibitors for mutated gastrointestinal stromal tumors. News release. Fox Chase Cancer Center. Published May 18, 2021. Accessed May 21, 2021. https://bit.ly/3wlMlqA

3. FDA approves avapritinib for gastrointestinal stromal tumor with a rare mutation. FDA. Published January 9, 2020. Accessed May 21, 2021. https://bit.ly/3wmm2Ra

4. 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