As mentioned above, imatinib has revolutionized the management of advanced GIST. Resistance however does develop in the majority of patients and the management of imatinib-resistant GIST remains a challenge. Dose escalation of imatinib may be supported for patients treated at 400 mg/day. However, responses to dose escalation tend to be relatively short-lived. Because of this there has been tremendous interest in strategies to manage imatinib-resistant GIST. Sunitinib, is currently the only FDA-approved therapy for patients with imatinib-resistant GIST. However, as with imatinib, resistance to sunitinib ultimately develops in most patients. Because of this, there remains intense interest in additional approaches to this disease.
A wide range of newer and more potent small molecule TKI that target KIT and/or PDGRA are in development. An agent with interesting single agent activity is sorafenib. Sorafenib is a multi-targeted small molecule TKI with potent activity against B-RAF tyrosine kinase, VEGFR, PDGFR, KIT, and FLT3 recently approved for use in patients with renal cell and hepatocellar carcinoma. In a phase II efficacy study carried out by the University of Chicago consortium, 26 patients with imatinib (6 patients) and sunitinib-resistant GIST (20 patients) were enrolled and treated with sorafenib 400 mg twice daily. Three (13%) and 14 (58%) out of 24 patients evaluable for response exhibited partial response and stable disease respectively, for a disease control rate of 71%. The median progression-free survival was 5.3 months.58
These results were supported by the recently reported European experience with sorafenib in this same patient population. In this retrospective study, thirty-two heavily pre-treated patients who failed imatinib, sunitinib and nilotinib were treated with sorafenib in the 4th-line setting. Nineteen percent of patients achieved a partial remission and 44% had disease stabilization. Median progression-free survival was 20 weeks and median overall survival was 42 weeks.59
These findings were corroborated in cell line models studying the in vitro activity of sorafenib against imatinib and/sunitinib-resistant kinases. The predominant mechanism of imatinib resistance is through the acquisition of secondary kinases as described. Sorafenib demonstrated significant activity in imatinib-resistant KIT
secondary mutations involving the ATP-binding pocket and activation loop. And notably, sorafenib unlike sunitinib is active against most imatinib-resistant secondary mutations involving the KIT
As the majority of patients in these studies had failed both imatinib and sunitinib, these results suggest that sorafenib may have promising activity in the treatment of GIST following imatinib and sunitinib failure.
Nilotinib is a second generation small molecule TKI with good activity against receptors of KIT and PDGFR. In a dose-finding phase I study, 53 GIST patients resistant to imatinib and other TKIs, were enrolled and treated with nilotinib alone (18 patients) or in combination with imatinib (35 patients). Although not designed as an efficacy study, one patient on single agent nilotinib had a partial response while 13 others had stable disease for a disease control rate of 78% a median progression-free survival of 5.6 months.61
Clinical trials are currently ongoing evaluating the benefit of nilotinib in the third line setting.
Similarly masitinib with reportedly greater affinity and selectivity for both the wild-type and mutated KIT than imatinib was investigated in a phase I dose-escalation study in patients with advanced and/or metastatic cancer. Half of the enrolled cohort had GIST. Treatment was generally well tolerated and the maximally tolerated dose was not determined in this study. One of 2 imatinib-intolerant patients demonstrated a partial response and about 29% of imatinib-resistant patients had stable disease.62
Building on these results, a multi-center phase II study of masitinib in treatment-naïve GIST patients led by the French Sarcoma Group was initiated. In a preliminary report 50% of patients demonstrated objective partial response (6.7% complete and 43.3% partial response), 47% had stable disease and 3% were primarily refractory to masitinib, yielding a overall disease control rate of 97%. The median progression-free survival was 27 months, comparable with imatinib.63
Phase III studies comparing nilotinib and masitinib as single agents with imatinib in the first line setting are now underway.
As discussed above there is substantial heterogeneity in the secondary mutations which render GIST resistant to TKIs. In addition, there may be pathways and strategies other than direct KIT inhibition, which are relevant to the biology of these tumors. Because of this, research efforts are focused on strategies which may be relevant in this disease other than direct KIT inhibition.
Heat shock protein-90 (HSP90) is an ATP-dependent protein chaperone involved in the regulation of cellular protein homeostasis. It regulates the stability of key proteins, including the KIT oncoproteins, important in oncogenesis, cancer cell proliferation, and cancer cell survival and plays a central role in protein folding in response to various environmental stresses.64
Pre-clinical work involving cell line models using 17-allylamino-18-demethoxy-geldanamycin (17-AAG), an inhibitor of the HSP90 chaperone protein, demonstrated significant reduction of both phospho- and total KIT expression, inactivation of downstream signaling pathways and inhibition of cellular proliferation and survival in both imatinib-sensitive and imatinib-resistant KIT-positive cell lines. Similar activity could not be demonstrated in a KIT-negative cell line suggesting that HSP90 inhibitor exerts its therapeutic function through its actions on KIT oncoprotein.65
Based on this preclinical rationale, a phase I/II study was conducted using IPI-504 (Retaspimycin Hydrochloride; Infinity Pharmaceuticals) in patients with metastatic, TKI-resistant GIST or metastatic soft tissue sarcoma.66
In the subset of 38 GIST patients, treatment was well tolerated; dose-limiting toxicities were headache and myalgia. Of the 18 GIST patients assessed by PET, 22% had a partial response and an additional 66% had stable disease according to the EORTC PET response criteria.67
Although no RECIST-defined responses were observed, approximately three-quarters of evaluable patients had stable disease as best response. This led to the initiation of an international phase III study in GIST. However the trial was closed early at the recommendation of an independent data monitoring committee due to safety concerns. Trials are now underway evaluating other HSP90 inhibitors in GIST. Additionally, in preclinical studies, PI3-kinase/mTOR pathways appear to be important in cell signaling and proliferation not only in imatinib-resistant cell lines but also in imatinib-sensitive and KIT-negative GIST.68
A number of PI3-kinase inhibitors and dual PI3-kinase/mTOR inhibitors are now in development and may prove to be effective in TKI-refractory GIST.
Combining agents that possess non-lapping toxicities targeting different aspects of the GIST cancer pathway in a synergistic fashion is another rationale approach to development of novel therapeutics. Based on in vitro
synergism demonstrated between imatinib and everolimus (previously known as RADOO1; Novartis Oncology) in human imatinib-resistant GIST cell lines, phase I/II clinical studies combining the 2 agents were performed. Primary study end point, defined as 4-month progression-free survival, was achieved in 17% (imatinib-refractory) and 37% (imatinib plus additional therapy) of patients prompting further studies into the various strategies of combined tyrosine kinase and mTOR inhibition.69