The clinical management of metastatic gastrointestinal stromal tumor (GIST) has greatly improved since the early 2000s. The approval of imatinib mesylate (Gleevec®) in 2002 by the US Food and Drug Administration (FDA) was a major turning point in the survival of patients with GIST. Since then, as mentioned by Drs. Patel and Reichardt, “a treatment algorithm for patients with advanced GISTs, which includes imatinib, sunitinib (Sutent®), and regorafenib (Stivarga®) as first-, second-, and third-line therapies, respectively, has been established.”
The success of GIST therapeutics is highly conditioned by the molecular heterogeneity of the tumors. Most (75%-80%) GISTs harbor gain-of-function mutations in the KIT gene. These mutations tend to occur in exon 11 (approximately 65%) and exon 9 (approximately 10%). Another GIST molecular subtype arises from mutations in the platelet-derived growth factor receptor alpha gene (PDGFRA). These mutations correspond to approximately 10% of GISTs and commonly occur in exon 18.
Approximately 10% to 15% of GISTs do not harbor either KIT or PDGFRA mutations; they are associated with genetic alterations in the RAS-MAPK pathway or succinate dehydrogenase deficiency. In addition, some GISTs are associated with oncogenic receptor tyrosine kinase (RTK) translocations, and others are devoid of any of the mutations mentioned.
Read more about GIST therapies
GISTs with KIT mutations in exons 11 and 9 are sensitive to imatinib mesylate, although responsiveness is better and overall survival with exon 11 mutations than with exon 9 mutations. In contrast, GISTs with the PDGFRA exon 18 D842V mutation, which account for 70% of mutant-PDGFRA cases, are resistant to imatinib mesylate. Sensitivity to imatinib mesylate is usually preserved in the remaining mutant-PDGFRA GISTs. Therefore, as Kelly et al discussed in a review published in the Journal of Hematology & Oncology, “knowledge of the molecular landscape in GIST is important because it provides prognostic information but also guides therapeutic selection.”
Conventional Tyrosine Kinase Inhibitors
Imatinib mesylate, sunitinib, and regorafenib are tyrosine kinase inhibitors used to treat GISTs. They differ in their safety profiles and efficacy against certain mutations.
Imatinib mesylate is a first-line therapy that targets 3 receptor tyrosine kinases: KIT, PDGFRA, and the BCR-ABL fusion oncoprotein. It can be used as adjuvant or neoadjuvant therapy, with an optimal daily dose of 400 mg. In 10-year follow-up data for imatinib mesylate, age younger than 60 years, small size of the largest lesion, and KIT mutations on exon 11 were associated with a better prognosis. Patients who respond well to this therapeutic are usually re-evaluated for surgical resection of residual disease. When progression is focal, clinicians have the option to treat the lesion locally and continue with the same drug scheme. On the other hand, if progression is diffuse, imatinib mesylate may be administered twice daily. However, this dosage can increase the number of adverse events.
The eventual development of secondary mutations during treatment results in failure of imatinib mesylate therapy. Secondary resistance to imatinib mesylate develops in approximately 40% of patients; in addition, in nearly 12% of patients, GISTs exhibit primary resistance to the drug. To manage these cases, the FDA approved sunitinib in 2006. Besides tyrosine kinase inhibitor activity, it also has anti-angiogenic activity. The recommended dose is 50 mg daily in a 4-weeks-on, 2-weeks-off schedule. Rates of response to sunitinib were higher in patients with KIT exon 9 mutations than in those with KIT exon 11 mutations (58% vs 34%, respectively). Nonetheless, “some patients develop mutations in the activation loop of the KIT gene and become resistant to further treatment; such mutations can shift the ratio of inactive KIT to active KIT and render sunitinib ineffective,” explained Drs. Patel and Reichardt.
Therefore, a third-line therapy, regorafenib, was approved years later. Besides KIT, regorafenib targets several other molecules. Like that of imatinib mesylate and sunitinib, the efficacy of regorafenib is affected by the mutational landscape. Treatment with regorafenib showed particular clinical benefit in patients with KIT exon 17 secondary mutations, as well as other mutations. In contrast, the efficacy of regorafenib against the KIT exon 13 V654A mutation is poor. Also, despite being effective against several amino acid substitutions on exon 17, it is ineffective against D816V.
Newly Approved Tyrosine Kinase Inhibitors
The FDA recently approved 2 additional tyrosine kinase inhibitors for the treatment of adults with advanced GIST: ripretinib (QINLOCK® in May 2020) and avapritinib (Ayvakit™ in January 2020).
Until the approval of ripretinib, no therapeutic option was available for patients who failed the first 3 lines of treatment. Ripretinib is a broad-spectrum KIT and PDGFRA kinase inhibitor with a dual mechanism of action that is effective against the full spectrum of primary and secondary drug-resistant mutations. Nonetheless, disease progression continues in many patients because of still-unidentified resistance mechanisms.
A daily dose of 150 mg was well tolerated, and the safety profile was similar after dose escalation to 150 mg twice daily. Therefore, ripretinib is an option when treatment-related toxicities or resistance develops. In fact, “although it is currently approved for use as a fourth-line or higher therapy in advanced GISTs, it is also under investigation for use as a second-line therapy in a randomized phase 3 study of ripretinib versus sunitinib,” said Drs. Patel and Reichardt.
Avapritinib was approved as a first-line therapy in patients with advanced GIST that harbor the PDGFRA exon 18 D842V mutation. It is about 10 times more potent than ripretinib against the D842V mutation. However, mechanisms of secondary resistance to avapritinib have been identified. These involve compound mutations in exons 13, 14, and 15 of PDGFRA; GISTs with these mutations show cross-resistance to all other drugs that inhibit PDGFRA.
What Is Next for the Treatment of Advanced GIST?
A number of additional therapeutic strategies have been explored in the context of advanced GIST, which include not only other kinase inhibitors but also immunotherapies, combination therapies, and alternating or cycling therapies. These studies now face an uncertain future because of the recent approval of ripretinib, but some have shown promising results (eg, cabozantinib [CABOMETYX®] and the combination of imatinib with interferon).
For instance, a phase Ib study evaluated the efficacy of the rapid alternation of sunitinib and regorafenib. The dose schedule consisted of repeated cycles of 3 days of sunitinib followed by 4 days of regorafenib. The recommended dose for phase II was 37.5 mg of sunitinib and 120 mg of regorafenib. “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,” Kelly et al said.
It is imperative to continue the investigation of advanced GIST therapeutics inasmuch as polyclonal resistance is still a major challenge.
Kelly CM, Gutierrez Sainz L, Chi P. The management of metastatic GIST: current standard and investigational therapeutics. J Hematol Oncol. 2021;14(1):2. doi:10.1186/s13045-020-01026-6
Patel SR, Reichardt P. An updated review of the treatment landscape for advanced gastrointestinal stromal tumors. Cancer. 2021;127(13):2187-2195. doi:10.1002/cncr.33630
Bauer S, George S, von Mehren M, Heinrich MC. Early and next-generation KIT/PDGFRA kinase inhibitors and the future of treatment for advanced gastrointestinal stromal tumor. Front Oncol. 2021;11:672500. doi:10.3389/fonc.2021.672500
ClinicalTrials.gov. Phase Ib study of sunitinib alternating with regorafenib in patients with metastatic and/or unresectable GIST (SURE). NCT02164240. https://clinicaltrials.gov/ct2/show/NCT02164240 Accessed October 3, 2021.