Next Generation of PDGFR Inhibitors Makes Headway in GIST

OncologyLive, Vol. 22/No. 10, Volume 22, Issue 10
Pages: 75

Dysregulated platelet-derived growth factor receptor signaling is implicated in a number of cancer types and is among the targets of many FDA-approved multikinase inhibitors.

Dysregulated platelet-derived growth factor receptor (PDGFR) signaling is implicated in a number of cancer types and is among the targets of many FDA-approved multikinase inhibitors.1,2 Despite the success of these drugs in a range of malignancies, it is difficult to know the contribution that PDGFR antagonism makes to their anticancer effects, particularly when other kinase targets, such as BCR-ABL and VEGFRs, have better-characterized roles in the pathophysiology of the cancer types for which these agents are approved.

The exception is gastrointestinal stromal tumors (GIST), in which PDGFR mutations are well-established drivers.3,4 Imatinib (Gleevec), which includes PDGFR among its targets, has been approved for the treatment of patients with KIT-positive unresectable or metastatic GIST, revolutionizing the treatment of this notoriously chemotherapy-resistant cancer.2,5

Over the years, several other multikinase inhibitors have been approved for the treatment of patients with GIST in an effort to tackle resistance to imatinib. However, none of these drugs targeted PDGFRA D842V, the most common PDGFR mutation observed in patients with GIST.1,2

That all changed in January 2020 when avapritinib (Ayvakit) became the first drug approved for the treatment of D842V-mutant GIST, demonstrating unprecedented durable responses in this patient population.6-8 In May 2020, ripretinib (Qinlock), which also targets the PDGFRA D842V mutation, gained FDA approval, ushering in a new generation of precision therapeutics for GIST.9,10

PROMISCUITY PAYS OFF

As prominent drivers of many of the hallmark capabilities of cancer that are readily druggable by small-molecule inhibitors, dysregulated kinases have been at the forefront of pharmaceutical research and development efforts in oncology for decades. The payoff has been paradigm shifts in the treatment landscapes for a range of cancers.11

Although many potent, highly specific inhibitors of a single oncogenic kinase have been developed, the story began in 2001 with a multitargeted drug. Imatinib, initially approved for the treatment of patients with chronic myeloid leukemia (CML), was hailed as a “magic bullet” for cancer and paved the way for the many kinase inhibitors that followed in its wake.12,13

Imatinib was developed as an inhibitor of the central oncogenic driver of CML, the BCR-ABL fusion protein, which results from a chromosomal rearrangement (dubbed the Philadelphia chromosome) that yields a fusion involving the ABL gene, which encodes a kinase. However, imatinib also was shown to have activity against a number of other kinases, including PDGFR.1,13

Capitalizing on this promiscuous activity, imatinib has been approved in multiple cancer types, including several in which PDGFR plays an oncogenic role.14 Dermatofibrosarcoma protuberans (DFSP) is a rare type of cutaneous soft tissue sarcoma. More than 90% of DFSP cases are characterized by chromosomal rearrangements that result in the COL1A1 gene fused to the PDGFB gene.15

Imatinib was approved by the FDA for the treatment of patients with DFSP in 2006 and, according to a recent systematic review, is associated with objective responses in more than 60% of advanced cases.15 Imatinib is also approved for the treatment of patients with chronic eosinophilic leukemia, which frequently displays a gene fusion between the FIP1L1 gene and the PDGFRA gene.11,16

The cancer type in which PDGFR has the most well-established role, however, is another rare form of sarcoma, GIST. The majority of GIST cases are defined by mutually exclusive gain-of-function mutations in either KIT or PDGFRA, both of which lead to constitutive activation of these kinases and the same downstream signaling pathways.3,4

Although KIT mutations dominate the genomic landscape of GIST, accounting for approximately 80% of cases, another 5% to 10% of patients harbor alterations in PDGFRA (FIGURE4). PDGFRA mutations in GIST typically involve exon 12, 18, or, more rarely, 14, which encode the juxtamembrane domain, activation loop, and adenosine triphosphate (ATP)–binding domain, respectively. PDGFRA-mutant GISTs often exhibit clinicopathologic differences from their KIT-mutant counterparts: they occur almost exclusively in the stomach, are more often epithelial in nature, and tend to be less aggressive.3,4,17

In 2002, imatinib received accelerated approval for the treatment of patients with KIT (CD117)-positive advanced/metastatic GIST, followed in 2008 by accelerated approval for adjuvant use in patients with resected KIT-positive GIST.18 Imatinib remains standard of care in both settings.

Imatinib has transformed the treatment of patients with GIST, who previously would have received an extremely poor prognosis.2 The majority of patients with GIST respond to imatinib; however, the development of resistance and resulting disease progression remain major obstacles, with approximately 50% of patients experiencing disease progression by 2 years after imatinib treatment begins and an estimated 10-year progression-free survival (PFS) rate of less than 10%.19

Resistance to imatinib often is driven by secondary mutations in KIT or PDGFRA. Two additional multitargeted kinase inhibitors that address some of these resistance mutations have been approved for the treatment of patients with advanced/metastatic GIST. Sunitinib (Sutent) and regorafenib (Stivarga) have been authorized for second- and third-line treatment, respectively.20,21

Sunitinib and regorafenib also target VEGFRs, highlighting another function of FDA-approved multikinase inhibitors as antiangiogenic agents. Angiogenesis, the formation of new blood vessels from existing vasculature, is regulated by a delicate balance between pro- and antiangiogenic factors within the cell. Dysregulated angiogenic signaling pathways, which lead to aberrant vasculature, are a hallmark of cancer.22-24

Both VEGFR and PDGFR signaling pathways play important roles in angiogenesis. A variety of multikinase inhibitors that target these receptors in addition to other kinases have proved effective against several cancer types, including highly vascularized tumors such as renal cell carcinoma and hepatocellular carcinoma. However, the contribution of PDGFR inhibi-tion to their efficacy remains unclear.22-24

THE NEXT GENERATION

In the past 20 years, the FDA has approved at least 12 kinase inhibitors that include PDGFR among their targets for oncologic indications in hematologic and solid tumors (TABLE 11,25-28).

The first drug that specifically targeted PDGFR to come to market was olaratumab (Lartruvo), which received accelerated approval from the FDA in 2016 for adult patients with certain subtypes of soft tissue sarcoma not amenable to curative treatment with radiotherapy or surgery. However, the indication was withdrawn in 2019 following a failed phase 3 trial.29-31

Ongoing clinical trials of kinase inhib-itors that target PDGFR more specifically are being conducted in biomarker-selected and unselected populations. Although devel-opment of approved multikinase inhibitors is ongoing in a range of tumor types with other targets, a study involving dasati-nib (Sprycel) in patients with gliomas with PDGFR mutations is underway (TABLE 2).

In GIST, research has focused on the most common PDGFRA mutation observed in the malignancy, which involves the substitu-tion of an aspartate with a valine at position 842 (D842V), which is located within exon 18. Tumors with this mutation are resistant to imatinib; thus, the majority of PDGFRA-mutant GISTs exhibit primary resistance to imatinib, making novel treatment options a high priority. Moreover, neither sunitinib nor regorafenib has activity in D842V-mutant GIST.32

A new generation of PDGFR inhibitors has been designed for the treatment of GIST, with the goal of blocking the activity of the D842V mutation. Imatinib, sunitinib, and regorafenib are all type II tyrosine kinase inhibitors; they bind to the inactive kinase and block its ability to become activated.1,33 As a type I inhibitor, avapritinib binds to the active conformation of the kinase. It has been shown to potently inhibit KIT and PDGFRA mutations, including activation loop mutations such as D842V.25 In January 2020, avapritinib became the first drug specifically approved for the treatment of patients with advanced/metastatic GIST with D842V and other PDGFRA exon 18 mutations.6

Approval was based on the results of the multicenter, single-arm, open-label phase 1 NAVIGATOR study (NCT02508532). A total of 82 patients enrolled across the dose- escalation and dose-expansion portions of the trial, 56 of whom had the D842V mutation (20 in dose escalation and 36 in dose expansion). During dose escalation, patients received doses ranging from 30 to 600 mg; in the dose-expansion phase, patients initially received a dose of 400 mg, which was reduced to 300 mg after a review of initial data.8

At a median follow-up of 15.9 months in the D842V population, the confirmed overall response rate (ORR) was 88%, and 9% of patients had a complete response. Common grade 1 or 2 treatment-related adverse events (TRAEs) at the 300-mg dose included nausea, diarrhea, decreased appetite, and fatigue. Across doses, grade 3 or 4 TRAEs occurred in 57% of patients, the most common of which was anemia.8

Long-term follow-up results for this study’s D842V group were recently published. At a median follow-up of 27.5 months, median overall survival (OS) had not yet been reached. With a median PFS of 34 months and ORR of 91%, avapritinib showed clinical activity deemed “unprecedented” by the study investigators. Additionally, TRAEs continued to be manageable.7

Meanwhile, the FDA denied a separate application for the approval of avapritinib for fourth-line treatment of patients with advanced/metastatic GIST. A complete response letter was issued after the phase 3 VOYAGER trial (NCT03465722), in which avapritinib was compared with regorafenib in patients with third- or fourth-line GIST regardless of tumor mutation status, failed to meet its primary end point of improved PFS. Median PFS was not significantly different between the 2 arms (4.2 months for avapritinib compared with 5.6 months for regorafenib).34,35

Ripretinib also is designed to inhibit a spectrum of KIT and PDGFRA mutations, including D842V, but with a mechanism of action distinct from that of avapritinib. Similar to imatinib, ripretinib is a type II inhibitor; it binds to the activation loop and locks PDGFR in an inactive conformation. However, ripretinib also binds to a “switch pocket” located in the ATP-binding domain, preventing it from interacting with the activation loop and thus providing an extra means of dampening kinase activity.10,26

The FDA approved ripretinib in May 2020 for fourth-line treatment of advanced/ metastatic GIST, based on the results of the phase 3 INVICTUS trial (NCT03353753), in which patients (N = 129) were randomized to receive either ripretinib or placebo. Ripretinib led to a significant improvement in median PFS (6.3 months compared with 1.0 month for placebo [HR, 0.15; 95% CI, 39.4-61.4; P < .0001]) and a numeric improvement in ORR (9.4% vs 0%; P = .050). Median OS was 15.1 months in the ripretinib arm compared with 6.6 months in the placebo arm (HR, 0.36; 95% CI, 0.21-0.62). However, due to the trial’s hierarchical testing of end points, the nonsignificant ORR meant that statistical significance of the OS data could not be formally tested. The most common TRAEs included alopecia, myalgia, nausea, fatigue, hand-foot syndrome, and diarrhea. Grade 3/4 TRAEs included increased lipase, hypertension, fatigue, and hypophosphatemia.9,19

Ripretinib is being compared with sunitinib as a second-line treatment option in the phase 3 INTRIGUE trial (NCT03673501), which has completed enrollment; top-line data are expected in the second half of 2021.36

Finally, crenolanib is a highly selective inhibitor of PDGFR and FLT3 that impedes both the wild-type and mutant forms of these 2 proteins, including the PDGFRA D842V mutation.37,38 It previously demonstrated a clinical benefit rate of 31% in a phase 1/2 trial in patients with advanced/ metastatic PDGFRA D842V-mutated GIST (NCT01243346),39 with in vitro activity against PDGFRA D842V (cellular IC50 9 nM), which prompted an ongoing phase 3 clinical trial in this patient population (NCT02847429).

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