New drugs in gastrointestinal stromal tumors
Javier Martin-Brotoa,b and David S. Mourab
INTRODUCTION
KIT and PDGFRa are dual-switch kinases: one located in the juxtamembrane domain with inhibi- tory function and encoded by exons 11 and 12 for KIT and PDGFRa, respectively; another located in the activation loop with activating function and encoded by exon 17/18 in KIT and 18/19 in PDGFRa. The most frequent primary KIT mutations (dele- tions, missense and insertions) in GIST, involves the exon 11 [1]; these mutations results in a loss- of-function of the inhibitory role of juxtamembrane domain [overall there is a gain-of-function of the tyrosine kinase receptor (TKI)]. This domain exerts auto-inhibition in the switch pocket in the activa- tion loop by Trp557, which induces the blockade of Phe811 to the nucleotide-binding site [2]. Then, mutations involving residues of this juxtamem- brane domain entails loss of inhibitory function in the activation loop. A small percentage of primary mutations and almost all the secondary resistance in GIST are gain-of-function mutations that stabilize the active type I conformation in the activation loop [3&&]. In more detail, mutations located in the ATP- binding pocket, encoded in KIT by 13/14 exons, have shown to be resistant to imatinib and regor- afenib, whereas mutations located in the activation loop, encoded in KIT by exon 17/18, exhibited imatinib and sunitinib resistance. The specific resis- tance mechanism is related to the conformational change induced by mutations that prevents, for instance, the entrance of the drug in the ATP-bind- ing pocket or is related to the fact that some type II inhibitors (imatinib or sunitinib) favor the juxta- membrane phosphorylated form over the fully phosphorylated form of KIT. In other words, these compounds exhibit lower potency in fully phosphorylated KIT type I state. Recently, the increasing knowledge derived from the conforma- tional status of KIT/PDGFRa, the way to stabilize active catalytic conformation and the function of the switch control lead to the appearance of new compounds [4,5,6&], profiled to overcome specific resistance in GIST [6&].Likewise, other drugs like immunotherapeutic agents, mitogen-activated protein kinase kinase 1/2 (MEK) inhibitors or tropomyosin receptor kinase (TRK)-targeted therapy have been tested in GIST with promising results in some specific set of patients.
TYROSINE KINASE INHIBITORS
Becoming new standards
Ripretinib: a switch control kinase inhibitor
Ripretinib, is a type II inhibitor designed to circum- vent the resistance related to the loss of inhibition, exerted by regulatory region in the activation loop. Part of ripretinib structure mimics the tryptophan residue that would had otherwise inhibited, inside the switch pocket, the activation loop in the absence of exon 11 mutation. Ripretinib is a novel drug that exerts its action mainly in the switch activator pocket in the activation loop, antagonizing the occupancy of the activation loop switch type I active state.
The kinome profile for ripretinib determined an inhibition with IC50 less than 10 nmol/l of the fol- lowing kinases: KIT, PDGFRa, DDR2, VEGFR2, PDGFRb and TIE2. Ripretinib inhibited phosphory- lation of KIT in all tested mutants that were resistant to imatinib and sunitinib, and exhibited three-fold to more than 50-fold more potent than regorafenib in 18 out of 37 KIT mutants tested, being the inhi- bition similar to regorafenib in other 17 out of 37 KIT mutants. Noteworthy, ripretinib was two-fold more potent than regorafenib in 21 out of 26 cell lines carrying KIT switch activating mutations in exons 17/18 and showed similar potency in the five remaining cell lines. Moreover, ripretinib was 10- fold to 20-fold more potent than regorafenib in the highly resistant D816V mutation of human mast cells (this mutation is structurally identical to D842V). Ripretinib also blocked proliferation of GIST cells with equal or greater potency than ima- tinib, sunitinib or regorafenib with the only excep- tion of T670I-resistant mutant GIST cell line, where sunitinib and regorafenib exhibited greater potency. Ripretinib also inhibited the proliferation of cells driven by PDGFRA variants, including the growth of Ba/F3 cells expressing D842V [3&&].
The phase I part of ripretinib enrolled patients with ECOG 0– 2 with refractory tumors carrying KIT or PDGFRA mutations, with special focus on GIST. Considering patients receiving at least 100 mg per day (n 178), 38 were treated at second-line, 29 at third-line and 111 at fourth or further lines. This latter subset showed an overall response rate (ORR) of 9% and a median progression free survival (mPFS) of 24 weeks [95% confidence interval (CI) 16–30], whereas those receiving ripretinib at second or third-line had an ORR of 21% and a mPFS of 40 weeks (95% CI 24-NE). Toxicity profile was mild and man- ageable. Alopecia was recorded in 50% of patients. Among patients receiving at least 100 mg per day, only 14 and 11% experienced dose reduction and discontinuation, respectively [7]. This encouraging clinical outcome led to two pivotal phase III trials (Table 1): INVICTUS (NCT03353753) for patients in at least fourth line versus placebo and INTRIGUE (NCT03673501) for patients in second line versus sunitinib, after imatinib failure (currently still accru- ing patients).
INVICTUS trial randomized 120 progressing GIST patients, at fourth line or further, in a 2 : 1 random assignment to receive ripretinib 150 mg daily or placebo. Stratification factors were: number of previous lines 3 versus at least 4 and ECOG status 0–1 versus 2. The main endpoint was mPFS accord- ing to RECIST 1.1 with blinded independent central radiological assessment. Secondary endpoints were ORR and overall survival (OS). The study was posi- tive, being the mPFS of 6.3 and 1 months for rip- retinib and placebo arm, respectively, hazard ratio 0.15 (95% CI 0.09– 0.25), P less than 0.0001. The RECIST-confirmed ORR was 9.4 versus 0% favoring ripretinib (P 0.0504). Even when formally was not performed, the OS was also significantly better in the ripretinib arm in spite of crossover: 15.1 versus 6.6 months for ripretinib and placebo, respectively, hazard ratio 0.36 (95% CI 0.20–0.60), P 0.0004. The fact of reporting just 1 month of mPFS in placebo arm, with an almost vertical drop in the treatment with imatinib, sunitinib and regorafenib.
Avapritinib: a type I active conformation inhibitor
Mutations in the activation loop entail shift towards active conformation in activation loop and induce resistance to type II TKIs (imatinib, sunitinib and regorafenib). Avapritinib was developed following the strategy to synthesize a type I inhibitor (a com- pound able to inhibit the active conformation in the activation loop). Avapritinib (formerly BLU-285) demonstrated substantial activity, in the subnano- molar range, for all activation loop mutants (encoded by exons 17/18 for KIT and 18/19 for PDGFRA). For mutations involving exons 11 and 17, it exhibited substantial activity. Of note, for D842V (the most frequent mutant of PDGFRa), avapritinib was the most potent in vitro inhibitor of cell proliferation and KIT phosphorylation [3&&,9]. Moreover, avapritinib showed superior activity than imatinib in most of the mutants tested, revealing a broader range of activity in this type I inhibitor than type II class inhibitors. However, the activity of avapritinib was weaker than imatinib in the ATP- binding pocket mutants (involving exons 13 and 14 of KIT gene) as T670I or V654A [9]. In PDX models was confirmed the same profile of activity. In a large analysis with three well characterized PDX models (harboring exons 11/17, 11 and 9 mutants), avapri- tinib showed significant antitumor activity, being superior than imatinib in exons 11/17 and 9 mutants and similar in exon 11 mutant. In the exons, 11/17 mutant avapritinib showed to be supe- rior to regorafenib as well [10&].
The study NAVIGATOR (NCT02508532), a first in-human study, had a phase I design with a dose- escalation part and an expansion part. In this latter, three cohorts were designed to explore the activity of avapritinib: in second line after imatinib, in third or further lines and in PDGFRA mutants. The rec- ommended phase II dose was 300 mg daily. Even when 25% of patients suffered at least grade 3 treat- ment-related toxicities, authors reported that the treatment was well tolerated. The most frequent adverse effects were fatigue (8%), hypophosphate- mia (6%) and anemia (4%) [11]. The ORR reported in patients harboring PDGFRA mutants (86% of them were D842V) was 86% from 42 evaluable patients, the median duration of response was not reached. Patients enrolled in a fourth or further line (n 111) exhibited an ORR of 22% and a median duration of response of 10.2 months. Grade 3 or 4-related adverse effects seen at least in 2% were anemia, fatigue, hypophosphatemia, hyperbilirubinemia, neutropenia and diarrhea. Of note, there were 29% of patients with grade 1 or 2 memory impairment (the most frequent cognitive side effect reported with avapritinib) [12]. With this data, avap- ritinib has been approved by Food and Drug Admin- istration (FDA) for treatment of metastatic or unresectable adult GIST patients harboring PDGFRA mutations in exon 18 including D842V mutation. Other indications as at least fourth line is submitted separately. In addition, the phase III VOYAGER trial (NCT03465722), which randomized patients in pro- gression after imatinib and one or two additional TKIs, to receive avapritinib versus regorafenib was recently closed. In a brief press release, the sponsor communicated VOYAGER trial did not meet the primary endpoint, showing no statistical significant differences in median mPFS: 4.2 vs 5.6 months for avapritinib and regorafenib, respectively.
Crenolanib: a type I selective PDGFRA- resistant mutant inhibitor
Crenolanib was profiled using KINOMEscan that quantitatively measured the ability of a compound to compete against an immobilized ligand. Creno- lanib was designed to have high selectivity of PDGFR kinases. In fact, it has 25-fold more affinity for PDGFRa/b than KIT. Crenolanib is specific inhibitor of type III tyrosine kinase receptor (as PDGFR, KIT and FLT3). Crenolanib showed to be more potent than imatinib in PDGFRA mutants involving activa- tion loop in exon 18: D842I, D842V or D842Y, specifically is roughly 135-fold more potent than imatinib for inhibiting the PDGFRA D842V muta- tion [13].
In a heavily pretreated GIST population carrying PDGFRA D842V mutation, crenolanib showed 31% clinical benefit rate with 35% of patients staying on study for at least 7 months. This outcome supported a phase III trial design comparing crenolanib 100 mg three times per day versus placebo. The main end- point is PFS and crossover is not allowed. The trial is currently enrolling patients with D842V mutation up to 120 individuals in a 2 : 1 random allocation [14].
Other tyrosine kinase inhibitors under research
Several TKIs are currently under preclinical or clini- cal research. Amongst these TKIs, Axitinib [15], AZD3229 [16] and cabozantinib [17] showed partic- ular activity in specific subsets of primary and/or secondary KIT mutations. Axitinib is an antiangiogenic agent that targets VEFGR1– 3, KIT and PDGFRa, with IC50 values sig- nificantly lower compared with pazopanib, sorafe- nib and sunitinib. In GIST primary cells, Axitinib showed higher efficacy against primary KIT mutations in codons 559 or 576, as well as in ima- tinib-resistant KIT secondary mutations T670I and V654A (ATP-binding pocket). In these models, Axi- tinib, was more active than imatinib, sunitinib and regorafenib [15].
AZD3229 is a quinazoline-derived Pan-KIT mutant inhibitor that has a modification in the C7-methoxyethoxy group that is critical to mediate the balance between efficacy upon KIT inhibition and VEGFR selectivity. VEGFR inhibition could lead to some significant toxicity, including high-grade hypertension; however, AZD3229 has shown to have manageable VEGFR-dependent effects, because of a lower activity on these receptors [16,18]. More- over, this small molecule has shown a rapid, wide and sustained inhibition of KIT or PDGFRa signaling in xenograft models, with tumor regressions ranging from 60 to 99%. The effect was seen in a board spectrum of KIT primary exon 11 deletions and primary/secondary ATP-binding pocket mutations. In line with these observations, it was recently reported in preclinical studies the superiority of AZD3229, in terms of potency and selectivity pro- file, compared with imatinib, sunitinib, and regor- afenib, as well as, avapritinib and ripretinib [19]. The clinical development of this drug is expected for the next years, with KIT-mutated GIST patients being the main target of this agent.
Cabozantinib is a TKI of MET, VEGFR, RET, AXL, KIT and FLT3 that has shown promising activity in GIST xenograft models bearing different KIT muta- tions (exons 9, 11 and 17) [20]. Recently, cabozan- tinib was tested in a phase II trial in GIST patients, progressing to imatinib and sunitinib: 24 out of 41 evaluable patients were progression-free at week 12 (the trial met its primary endpoint) [21]; however, further explorations are necessary to describe, which GIST subset of patients benefit the most from cabozantinib treatment.
MEK INHIBITORS
MEK inhibition alone seems to be ineffective in GIST, mainly because of the reactivation of upstream tyrosine kinases receptors, such as KIT or PDGFRa, induced by MEK inhibitors [22,23]. Nevertheless, preclinical evidence have shown that the dual inhibition of KIT and MAPK was synergistic [24]. This strategy was tested in a phase I trial, in which GIST patients, progressing to imatinib were treated with a MEK inhibitor (binimetinib) com- bined with a potent inhibitor of CSF1R, KIT and FLT3 (pexidartinib). Two patients (out of two) treated with this combination, displayed prolonged stabilization: PFS of 6.1 in a patient carrying an exon 11 KIT-mutated GIST and more than 19 months in a patient bearing a NF-1-mutated GIST [22]. However, and since pexidartinib preferentially targets KIT exons 13 and 14, it should be relevant to test this agent in patients bearing these mutations. Also, it is important to define if the prolonged stabilization in NF-1-mutated GIST could be achieved with MEK inhibitors in monotherapy, as this set of patients may respond to MEK inhibitors in monotherapy [25].
IMMUNOTHERAPY
Preclinical evidences suggest that the characteristics of the immune infiltrate could affect GIST prognosis [26] and response to imatinib [27], indicating that immunotherapy could have a role in the treatment of GIST. In line with this, several clinical trials were designed in GIST to test the activity of immune- checkpoint blockade in patients progressing at least to imatinib. In a randomized phase II trial of nivo- lumab versus nivolumab with ipilimumab, 1 patient out of 12 (8.3%) had a partial response and 2 out of 12 (16.7%) had SD in the combination arm, while 7 SD were seen among 15 patients (46.7%) treated with nivolumab. The mPFS in the nivolumab and in combination arm were 8.57 and 9.10 weeks, respectively. Eight patients continued on therapy for more than 6 months. Of note, two patients carrying KIT exon 17 mutation had tumor shrink- age, suggesting that this set of patients may benefit from immunotherapy [28]. The percentage of responses seen in this trial is line with data previous published with the combination of ipilimumab and imatinib; in this latter study 1 out of 12 GIST patients (8.3%) responded to immunotherapy regi- mens [29]. On the other hand, it is also important to consider the upregulation of LAG3 and TIM-3 on the tumor-infiltrating lymphocytes that has been reported in GIST [30,31]. Immune-checkpoint inhibitors, such as anti-TIM-3 antibodies (e.g. LY3321367 or MBG453) or anti-LAG3 antibodies (e.g. relatlimab or ieramilimab) should be contem- plated for future clinical trials in GIST.
TARGETED THERAPY FOR GASTROINTESTINAL STROMAL TUMOR WITH NTRK FUSION PROTEINS
Fusions constituting tropomyosin receptor kinases (TRK) can be found in SDH-competent wild-type GIST, which suggests that TRK fusion-positive GIST could be sensitive to highly selective TRK inhibitors. Noteworthy, it was recently reported that three out of three TRK fusion-positive GIST patients treated with larotrectinib responded to therapy, confirming the efficacy of TRK fusion-targeted therapy in this set of patients [32&]. However, further studies should validate these results in larger series of patients to provide more detailed clinical data about the dura- tion of the response and survival.
CONCLUSION
New potent TKIs, as ripretinib and avapritinib, are being approved by regulatory agencies in advanced GIST contexts with unmet need. Crenolanib could also add value in specific PDGFRa-resistant mutants. Other agents, such as MEK inhibitors, immunother- apy and TRK-targeted therapy are potential new options in specific subsets of GIST patients.
Acknowledgements
None.
Financial support and sponsorship
None.
Conflicts of interest
J.M.B. reports research grants from PharmaMar, Eisai, Immix BioPharma and Novartis outside the submitted work; honoraria for advisory board participation and expert testimony from PharmaMar, honoraria for advi- sory board participation from Eli Lilly and Company, Bayer and Eisai; and research funding for clinical studies (institutional) from PharmaMar, Eli Lilly and Company, Bayer, Eisai, Lixte, Karyopharm, Deciphera, GSK, Novartis, Blueprint, AROG, Nektar, Forma, Amgen and Daiichi Sankyo. D.S.M. reports institutional research grants from PharmaMar, Eisai, Immix BioPharma and Novartis outside the submitted work; travel support from PharmaMar, Eisai, Celgene, Bayer and Pfizer.
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