Imatinib-sensitive GIST: first line therapy
Imatinib is a selective, small molecule inhibitor of three receptor tyrosine kinases: the transmembrane receptor
KIT, the chimeric
BCR-ABL fusion oncoprotein of chronic myeloid leukemia and
PDGFRA. In 2002, the FDA approved imatinib for the management of patients with advanced GIST. This accelerated approval was based on the results of a multi-center, randomized study that evaluated the safety and efficacy of imatinib at two dose levels (either 400 mg and 600 mg daily) in 147 patients with advanced GIST [
8]. The clinical benefit rate of imatinib was 81%; with 53.7% of patients achieving a RECIST partial response. The median time to an objective response was 3 months. Almost 14% of patients had early progressive disease despite imatinib therapy. No complete responses were observed. The majority of patients experienced mild to moderate adverse effects. The most common adverse events included edema (74%, frequently periorbital in location), nausea (52%), diarrhea (45%), myalgia or musculoskeletal pain (40%), fatigue (35%), dermatitis or rash (31%), headache (26%) and abdominal pain (26%).
The optimal imatinib dose (400 mg daily) to use in the first line setting was determined in two-phase III trials that randomized patients with advanced GIST to receive imatinib at 400 mg or 800 mg daily. The EORTC 62005 trial enrolled 946 patients. The higher imatinib dose arm yielded a statistically significant progression free survival (PFS) rate of 56% versus 50% for the lower dose arm, (estimated hazard ratio 0.82 [95% CI 0.69–0.98];
p = 0.026) [
10]. The overall response rates were similar between the two treatment arms. The higher dose arm was associated with greater toxicity. The SWOG S0033/CALGB 15105 trial enrolled 746 patients. After a median follow-up of 4.5 years, no significant difference was observed with respect to median PFS (18 vs. 20 months), median OS (55 vs. 51 months) and objective response rate (40% vs. 42%), between the standard dose and the higher dose arms, respectively [
11].
In the EORTC 62005 trial, the strongest prognostic factor of risk for progression and death was the presence of a
KIT exon 9 mutation. In patients with KIT exon 9 disease, the PFS was significantly longer in patients that received double-dose imatinib compared to those that received the standard dose. For patients that crossed over to double-dose imatinib, the response rates observed were significantly higher among patients with
KIT exon 9 (57%) compared to
KIT exon 11 (7%) mutant disease. The phase III SWOG S0033/CALGB 15105 trial failed to demonstrate a PFS benefit favoring the
KIT exon 9 mutant cohort that received the higher dose imatinib. However, it did show improved response rates in the
KIT exon 9 mutant cohort compared to the
KIT exon 11 mutant cohort that crossed over to receive double-dose imatinib (67% vs. 17%, respectively). A preplanned meta-analysis of both the EORTC 62005 and SWOG S0033/CALGB 15105 studies confirmed a PFS advantage in favor of patients with
KIT exon 9 mutant disease who received double-dose imatinib (400 mg, twice daily) compared to standard dose [
12]. As a result, the standard dose for patients with
KIT exon 9 mutant advanced GIST receiving first-line imatinib is 400 mg twice daily.
Imatinib refractory GIST
Sunitinib is another small molecule, receptor TKI. It targets
KIT/PDGFRα, colony stimulating factor 1 receptor (CSF1R), Fms-related tyrosine kinase 3,
RET and has anti-angiogenic activity by inhibiting vascular endothelial growth factor receptors (
VEGFR1-3). An early phase study provided safety and promising efficacy data for sunitinib (50 mg, 4 weeks on, 2 weeks off schedule). This led to a randomized, double-blind, placebo-controlled, phase III trial of sunitinib in patients with advanced, imatinib refractory/intolerant GIST. The objective response rate with sunitinib was 7% (RECIST partial response). However, the study demonstrated a significantly longer time to progression, based on RECIST criteria, of 27.3 weeks versus 6.4 weeks in the placebo arm;
p < 0.0001) [
13]. FDA approved sunitinib in the management of advanced GIST in 2006. Another phase II study examined the benefit of an alternative dosing schedule of sunitinib delivered on a continuous, daily basis (37.5 mg once daily) to patients with advanced, imatinib refractory GIST. The clinical benefit rate was 53%, and median PFS was 34 weeks. Most adverse events encountered were ≤ grade 2 in severity and manageable. Morning or evening dosing was comparable with respect to efficacy and safety [
14]. A continuous daily dosing schedule of sunitinib is commonly used to treat patients with advanced GIST.
The GIST molecular genotype has been shown to correlate with efficacy of sunitinib. Higher response rates were observed among GIST patients treated with sunitinib that harbored primary
KIT exon 9 mutations compared to
KIT exon 11 mutations (58% vs. 34%, respectively). Among patients with advanced GIST treated with sunitinib alone, longer PFS and OS were seen for those with exon 13 or 14 secondary
KIT mutations compared to those with exon 17 or 18 secondary
KIT mutations [
15].
Regorafenib is another oral multi-targeted kinase inhibitor that targets a number of pathways involved in tumor growth including tumor angiogenesis (
VEGFR-1, -2, and -3, and
TIE2), oncogenesis (
KIT, RET, RAF-1, BRAF and BRAFV600E), and the tumor microenvironment [PDGFR and fibroblast growth factor receptor (FGFR)]. The safety of regorafenib was first demonstrated in a phase I study that enrolled an unselected population of patients with solid tumors. This study confirmed the recommended phase II dose of 160 mg daily (3 weeks on, 1 week off schedule) [
16]. A phase II GIST specific study investigated the efficacy of regorafenib among 34 patients with advanced GIST who had previously progressed on at least imatinib and sunitinib. The clinical benefit rate observed was 79% (4 patients achieved a partial response and 22 patients had stable disease at ≥ 16 weeks). The median PFS was 10 months [
17]. Regorafenib was subsequently investigated in a phase III study that randomized 240 patients with advanced GIST to receive regorafenib versus placebo plus best supportive care in a 2:1 fashion. The study met its primary endpoint by demonstrating a significant improvement in median PFS (4.8 months and 0.9 months, respectively (hazard ratio [HR] 0.27, 95% confidence interval [CI] 0.19–0.39;
p < 0·0001). A best response of partial response or stable disease was observed in 75.9% on regorafenib and 34.8% in the placebo arm. The disease control rate was also higher in the regorafenib arm compared to placebo, (52.6% and 9.1%, respectively) [
18]. In 2013, the FDA approved regorafenib for use in the management of patients with advanced GIST refractory to imatinib and sunitinib.
A recent phase Ib trial tested the efficacy of rapid alternation of sunitinib and regorafenib: 3 days of sunitinib followed by 4 days of regorafenib, and repeated. Toxicity was encountered at the previously determined optimal doses of both agents. The recommended phase II dose was identified as sunitinib 37.5 mg and regorafenib 120 mg. Stable disease was the best response observed in 4 out of 14 participants. The median PFS was 1.9 months. Rapid alternation of tyrosine kinase inhibitors (TKIs) was an unprecedented investigational approach in GIST that may prove effective when drugs with complementary pharmacokinetics are combined in an effort to minimize toxicity while allowing optimal drug doses to be used [
19].
Ripretinib is a potent switch pocket control inhibitor of KIT and PDGFR kinases and has activity against a broad range of mutations. The phase I study enrolled 142 patients with advanced GIST with
KIT (95%) or
PDGFRα (5%) mutations. The recommended phase II dose of ripretinib was 150 mg once daily. The ORR in second-, third- and fourth-line patients was 19.4%, 14.3% and 7.2%, respectively [
20]. The INVICTUS, phase III, randomized, double-blind, placebo-controlled trial randomized 154 patients with advanced GIST in a 2:1 fashion to receive ripretinib or placebo. GIST patients had progressed on or were intolerant of imatinib, sunitinib and regorafenib. The study met its primary end point showing a significant improvement in median PFS favoring the ripretinib arm [6.3 months vs. 1·0 months (hazard ratio 0.15, 95% CI 0.09–0.25;
p < 0.0001)]. The median OS was 15.1 months in the ripretinib group compared to 6·6 months in the placebo group (HR 0.36, 95% CI 0.21–0.62). Ripretinib yielded an objective response rate (ORR) of 9%. There was no response observed in the placebo arm. Ripretinib was generally well tolerated. The most common (≥ 20% of patients in the ripretinib group) treatment-related adverse events were alopecia, myalgia, nausea, fatigue, palmar–plantar erythrodysesthesia and diarrhea [
21]. In May 2020, the US FDA approved ripretinib for patients with advanced GIST that had progressed on three or more receptor tyrosine kinase inhibitors including imatinib [
22]. Intrigue, a phase III trial examining the efficacy of ripretinib compared to sunitinib in patients with advanced GIST who have progressed on or are intolerant of imatinib in the second line setting is currently ongoing [
23].
Primary imatinib-resistant GIST/PDGFRA D842V-mutant GIST: first line therapy
PDGFRA-mutant GIST accounts for 5–10% of GIST and exhibits primary resistance to imatinib and sunitinib therapy. The median PFS of
PDGFRα D842V mutant advanced GIST on placebo from retrospective analysis was reported to be 2.8 months [
24]. Notably, the median PFS of unselected patients with GIST on placebo is less than 6 weeks [
13,
18]. This highlights that
PDGFRA D842V mutant GIST is clinically distinct from imatinib-sensitive disease. It often follows a more indolent disease course. Until January 2020, there was no standard of care systemic therapy available for this GIST molecular subtype and surgical resection was preferred in the setting of small volume disease progression. In a phase II trial, dasatinib yielded a response in one patient with
PDGFRA D842V-mutant GIST. Based on this preliminary efficacy, dasatinib was added to NCCN compendium of approved agents for this molecular subtype [
25].
Avapritinib is a potent, highly selective oral inhibitor of
PDGFRα mutant kinases. The Navigator, phase I dose escalation/dose expansion study enrolled 231 patients with advanced GIST:
PDGFRA exon 18
D842V mutant = 56 (24%), non-
D842V mutant = 8 (4%) and
KIT mutant disease = 167 (72%). In the
PDGFRA D842V-mutant population, the ORR was 88%. There were five (9%) complete responses and 44 (79%) partial responses. The clinical benefit rate was 98%, which is remarkable in a GIST molecular subtype that was known to be refractory to all previously FDA-approved TKIs for GIST [
26]. Avapritinib was generally tolerated. Cognitive effects emerged as an adverse event of special interest. Most cognitive effects, primarily driven by memory impairment, were grade 1 and generally manageable with dose modification. However, 8.3% of patients discontinued avapritinib for a treatment-related toxicity, of which 2% discontinued treatment because of intracranial bleeding [
26]. The recommended phase II dose was determined to be 300 mg once daily and the FDA approved avapritinib in January 2020 for adults with inoperable GIST harboring a
PDGFRA exon 18 mutations, including the
D842V mutation.