A combination of imatinib and alpelisib as a third-line treatment in patients with an advanced gastrointestinal stromal tumor (GIST) demonstrated an acceptable safety and tolerability profile but initial evidence does not justify additional testing, researchers reported in BMC Cancer.

Tyrosine kinase inhibitors, such as imatinib, are key drugs for use against KIT-mutated GISTs. Imatinib is considered first-line therapy due to research confirming its ability to extend both progression-free survival and median overall survival. However, the evidence for an appropriate second- and third-line therapy for GIST is still lacking; candidates such as sunitinib and regorafenib perform significantly poorer than imatinib. 

In addition, acquired resistance to tyrosine kinase inhibitors can result in unrestrained disease progression, often leading to mortality. Studies have demonstrated that the PI3K pathway plays an important role in the survival of patients who are resistant to imatinib.


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Hence, the authors of this study hypothesized that a PI3K inhibitor, such as alpelisib, used in combination with imatinib might improve the clinical outcomes of patients who do not respond well to existing systemic therapies. 

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The research team recruited 56 patients with unresectable and metastatic GIST who had not responded well to imatinib or sunitinib and showed disease progression despite being on these medications. The participants were prescribed alpelisib (in increasing doses from 200 mg to 250 mg and 350 mg once daily) together with imatinib 400 mg once daily until the maximum tolerated dose was reached. 

The results demonstrated that 100% of participants experienced adverse events on this combination of drugs at some point in the study, the most common being nausea and hyperglycemia. In addition, this combination treatment demonstrated a median progression-free survival of only 2 months, which does not compare favorably with other available tyrosine kinase inhibitor monotherapies.

“Our results suggest limited clinical activity . . . the combination did not demonstrate sufficient clinical activity to justify additional clinical testing,” the authors of the study wrote.

Reference

Pantaleo MA, Heinrich MC, Italiano A, et al. A multicenter, dose-finding, phase 1b study of imatinib in combination with alpelisib as third-line treatment in patients with advanced gastrointestinal stromal tumorBMC Cancer. 2022;22(1):511. doi:10.1186/s12885-022-09610-4