Gastrointestinal stromal tumours (GIST) are commonly driven by activating mutations in the KIT or PDGFRA receptor tyrosine kinases. Although the initial response rates for newly diagnosed GIST to the tyrosine kinase inhibitor(TKI) imatinib can be _ 50%, most tumours ultimately become resistant, commonly through secondary mutations or through alternative pathways.Mutated forms of KIT and PDGFRA are reliant onthe heat-shock protein 90 (HSP90) chaperone for their functional stabilisation.
Inhibition of HSP90 function causes degradation of KIT in vitro and inhibits tumour growth in GIST models. In a phase 1 trial of the geldanamycin analogue HSP90 inhibitor IPI-504, stable disease (assessed by RECIST 1.0) was observed in 70% of patients with metastatic and/or unresectable GIST (n Z 37), with one partial response;metabolic partial responses were observed in 38% of these patients. In a phase 2 trial of the nonansamycin HSP90 inhibitor BIIB021, stable disease(assessed by RECIST 1.0) was observed in 43% of patients with GIST refractory to imatinib and sunitinib,with a 22% metabolic partial response rate.
Onalespib is a potent non-ansamycin HSP90 inhibitor that shows activity in many preclinical models, including imatinib-sensitive and -resistant GIST. Preliminary antitumour activity was observed in patients with GIST in a phase 1 study of onalespib monotherapy.
The combination of onalespib with imatinib was well-tolerated inmice and was shown to inhibit tumour growth in a TKI-resistant model. Here, we describe a phase 1 study investigating the safety and efficacy of onalespib in combination with imatinib in patients with GIST.Imatinib was given in combination with onalespib for the possibility that a subpopulation of tumour cells may still be sensitive to imatiniband that combining partial kinase inhibition with reduced KIT levels would lead to a synergisticor additive decrease in oncogenic KIT signalling.
Patients included in the study were _ 18 years of age,ECOG performance status 0 or 1, with unresectable and/or metastatic GIST with objective progression of disease following previous treatment with a maximum ofthree TKIs, including imatinib. The trial was carried outin accordance with the Declaration of Helsinki. All patients provided written informed consent and the study was approved by local institutional review boards.
A standard 3+3 dose-escalation design was used todefine the MTD of intravenous (i.v.) onalespib administered once weekly for 3 weeks of each 4-week cycle in combination with daily oral imatinib (400 mg).Four sequential dose levels were tested following safety monitoring committee (SMC) recommendations:180 mg/m2 (Cohort 1), 150 mg/m2 (Cohort 2), 180 mg/m2 (Cohort 3), and 220 mg/m2 (Cohort 4). Patients who exhibited evidence of clinical benefit and continued tomeet the eligibility criteria were allowed to remain onstudy until they withdrew consent or experienced disease progression or until the study was terminated.
The MTD of on alespib in combination with standard dose imatinib was not reached, as the study was closed early. The highest dose of onalespib that was safely administered in combination with imatinib in patients with baseline normal renal function was 220 mg/m2 once weekly for 3 weeks of every 4-week cycle. Treatment with the combination of onalespib and imatinib was well tolerated, and treatment-related toxicities were consistent with those previously reported following single agenttherapy with either imatinib or onalespib. The appearance of renal toxicity following a relatively low dose of onalespib was unexpected, but may have been due to pre-existing renal impairment or vascular disease.In this exploratory dose-finding study, combination therapy achieved limited efficacy in TKI-resistant GIST.