Avapritinib Does Not Show PFS Benefit Over Regorafenib in Late-Line GIST, But Remains Active Option for Select Subset

Avapritinib did not improve progression-free survival vs regorafenib in patients with unresectable or metastatic gastrointestinal stromal tumors, but the agent continues to be the most active available option for a subset of patients with PDGFRA D842V–mutant disease.

Avapritinib (Ayvakit) did not improve progression-free survival (PFS) vs regorafenib (Stivarga) in patients with unresectable or metastatic gastrointestinal stromal tumors (GIST), but the agent continues to be the most active available option for a subset of patients with PDGFRA D842V–mutant disease, according to data from the phase 3 VOYAGER trial (NCT03465722) published in the Journal of Clinical Oncology.1

The median PFS with avapritinib was 4.2 months vs 5.6 months with regorafenib (HR, 1.25; 95% CI, 0.99-1.57; P = .055). However, among a subset of patients with PDGFRA D842V–mutant GIST (n = 13), the median PFS was found to be significantly higher with avapritinib vs regorafenib; it had not been reached (95% CI, 9.7–not reached [NR]) in the investigative arm vs 4.5 months (95% CI, 1.7–NR) in the control arm (P = .035).

When the 13 patients in this subset were excluded from the intent-to-treat (ITT) population, the median PFS was found to be statistically higher with regorafenib compared with avapritinib, at 5.6 months vs 3.9 months, respectively (HR, 1.34; 95% CI, 1.06-1.69; P = .012).

“Avapritinib was not superior to regorafenib in terms of median PFS in third-line or later treatment of patients with molecularly unselected unresectable or metastatic GIST in the VOYAGER study,” Yoon-Koo Kang, MD, PhD, of the Department of Oncology at the Asian Medical Center of the University of Ulsan College of Medicine, and colleagues, wrote. “As expected, avapritinib demonstrated a high objective response rate [ORR] and prolonged duration of response [DOR] in a subgroup of 7 patients with PDGFRA D842V–mutant GIST.”

In May 2020, the FDA issued a complete response letter to Blueprint Medicines Corporation stating that it will not approve a new drug application for avapritinib for use in the treatment of adult patients with unresectable or metastatic fourth-line GIST based on data from VOYAGER.2

In the open-label, multicenter, phase 3 VOYAGER trial, investigators compared the safety and efficacy of avapritinib with regorafenib in patients with unresectable or metastatic GIST who were at least 18 years of age, had received prior imatinib (Gleevec) and 1 or 2 additional TKIs, and who had an ECOG performance status of 0 or 1.

If patients previously received avapritinib, regorafenib, or over 3 different TKIs, they were excluded. Other exclusion criteria comprised having received systemic anticancer therapy or radiotherapy within 2 weeks prior to randomization or known risk of intracranial bleeding within 1 year prior to randomization.

A total of 476 participants were randomized 1:1 to receive either oral avapritinib at a daily dose of 300 mg in continuous 28-day cycles (n = 240) or oral regorafenib at a once-daily dose of 160 mg in 28-day, 3-weeks-on and 1-week-off cycles (n = 236). Patients were stratified by TKI treatment (third line vs fourth line), geographic region (Asia vs other countries), and PDGFRA D842V status (mutation present vs absent) measured via circulating tumor DNA (ctDNA).

Notably, patients in the investigative arm had the option to escalate to a once-daily dose of 400 mg per investigator discretion after certain criteria were satisfied. Crossover from the placebo arm to the investigative arm was permitted for participants who had centrally confirmed radiologic disease progression.

The primary end point of the trial was PFS based on central radiologic assessment and RECIST v1.1 criteria modified for GIST. Important secondary end points comprised ORR per modified RECIST v1.1 criteria, OS, safety, disease control rate, complete and partial response rates, and DOR per central radiology assessment and modified RECIST v1.1 criteria.

All participants who received avapritinib started with the 300-mg dose and 4 of these patients escalated to the 400-mg dose. All patients who received regorafenib started at a dose of 160 mg. Of the 236 patients on the regorafenib arm, 41.9% crossed over to receive avapritinib.

The median age of patients in the ITT was 61 years (range, 31-91), 66.8% were male, 59.2% were White, and 25.4% were from Asia. All participants previously received imatinib, 95.0% received prior sunitinib (Sutent), 85.7% received 2 distinct prior TKIs, and 14.3% previously received 3 distinct TKIs.

Baseline ctDNA showed that 3.8% of patients harbored a PDGFRA exon 18 mutation; 30.7% had mutations other than PDGFRA exon 18, KIT V654A, KIT T670I, or KIT exon 17; 2.7% had a D842V mutation in the activation loop sequence of PDGFRA exon 18. Additionally, for 28.6% of patients, the mutation status in the ctDNA was unknown.

Additional data from the trial indicated that no significant difference in median PFS was observed between the subsets of patients who received avapritinib vs regorafenib as third-line treatment, at 4.2 months vs 5.5 months, respectively (HR, 1.26; 95% CI, 0.98-1.61; P = .068); this was also true for when the agents were received in the fourth-line setting, at 3.8 months and 5.6 months, respectively (HR, 1.19; 95% CI, 0.66-2.15; P = .550).

The median PFS in participants from Asia was comparable to that in other countries, with no significant difference reported between avapritinib and regorafenib, at 3.9 months vs 5.4 months, respectively (HR, 1.14; 95% CI, 0.72-1.80; P = .583).

In patients who crossed over from the control arm to the investigative arm (n = 99), the median investigator-assessed PFS was 2.6 months (95% CI, 1.84-3.71), and the PFS rate at 6 months was 24.1%.

The OS data were immature at the time of the data cutoff, and at a median follow-up of 8.5 months and 9.6 months for avapritinib and regorafenib, respectively. At 12 months, the estimated OS rates were comparable between the 2 agent in the ITT population, at 68.2% vs 67.4%, respectively. Among patients treated in the third-line setting, these rates were 67.9% and 68.8%, respectively; in the fourth-line setting, these rates were 67.4% and 60.4%, respectively.

In the ITT population, avapritinib elicited a significantly higher ORR than regorafenib, at 17.1% (95% CI, 12.5%-22.5%) and 7.2% (95% CI, 4.3%-11.3%), respectively (P < .001). The median DOR in the investigative and control arms were 7.6 months (95% CI, 5.6–NR) and 9.4 months (95% CI, 7.4–NR). The ORR was still significantly higher with avapritinib even when the subset of patients with PDGFRA D842V were excluded (P < .003, and in those who received third-line treatment (P < .001). No difference was observed in those who received fourth-line treatment.

In the 7 patients with PDGFRA D842V–mutated disease, avapritinib induced an ORR of 42.9% (95% CI, 9.9%-81.6%). None of the patients who harbored this mutation and received regorafenib experienced a radiologic response to treatment.

Regarding safety, the incidence of any-grade treatment-related adverse effects (TRAEs) proved to be comparable between the investigative and control arms, at 92.5% and 96.2%, respectively; 55.2% vs 57.7% of patients, respectively, had effects that were grade 3 or higher.

The most frequent any-grade TRAEs experienced by 30% or more patients who received avapritinib included anemia (40.2%), nausea (39.3%), and fatigue (35.1%); with regorafenib, the most common toxicities were fatigue (34.2%), diarrhea (34.6%), and palmar-plantar erythrodysesthesia syndrome (59.0%).

Moreover, 8.3% of patients who received avapritinib discontinued treatment due to TRAEs vs 5.6% of those who were given regorafenib. Sixty-six percent of patients who crossed over from the control arm to the investigative arm discontinued treatment. Reasons for discontinuation comprised progressive disease (36.4%), toxicities (10.1%), clinical progression (7.1%), administrative or others (6.1%), withdrawn consent (3.0%), investigator decision (2.0%), and patient refusal (1.0%).


  1. Kang Y-K, 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 3, 2021. doi:10.1200/JCO.21.00217
  2. Blueprint Medicines receives complete response letter from FDA for avapritinib new drug application for the treatment of fourth-line gastrointestinal stromal tumor. News release. Blueprint Medicines. May 15, 2020. Accessed August 5, 2021. https://bit.ly/2T9c58n