Correlation of KIT and PDGFRA mutational status with clinical benefit in patients with gastrointestinal stromal tumor treated with sunitinib in a worldwide treatment-use trial

Gastrointestinal stromal tumors (GIST) comprise the most common primary mesenchymal malignancies of the gastrointestinal tract, and approximately 95 % of these tumors express the cell-surface transmembrane receptor KIT that has tyrosine kinase activity [1]. Constitutive activation of KIT occurs in approximately 80–85 % of cases through mutations at various sites in the transcribed sites of the KIT proto-oncogene [1]. This is one of the earliest cellular events responsible for the oncogenic transformation of GIST cells and is a key driver of the disease pathogenesis [2, 3]. Mutations occur most commonly in exon 11 (juxtamembrane domain), followed in frequency of incidence by exon 9 (extracellular domain) [1]. Activating mutations also occur in the PDGFRA gene (encoding the receptor tyrosine kinase platelet-derived growth factor receptor [PDGFR]-α) in approximately 5–7 % of GIST cases. These often occur mutually exclusively to KIT mutations, highlighting their important role in the pathogenesis of GIST [4]. Finally, there is a subset of 12–15 % of GIST cases which lack mutations in KIT and PDGFRA but which often harbor genomic or epigenetic aberrations in subunits of the succinate dehydrogenase (SDH) complex [5].

Imatinib is a relatively selective small molecule inhibitor of a limited number of tyrosine kinases—including KIT, PDGFRA, and the intracellular ABL kinase—that has helped to transform the management of GIST. It was approved for the treatment of metastatic or unresectable GIST in the USA in 2002, following a successful phase II trial and follow-up period [6, 7]. However, the clinical benefits observed in GIST patients with imatinib vary according to KIT and PDGFRA genotype. For example, patients with KIT exon 11-mutant GIST have a greater objective response rate (ORR) and longer median progression-free survival (PFS) with front-line imatinib treatment than GIST patients with KIT exon 9-mutant or KIT/PDGFRA “wild-type” (non-mutant) genotypes [8, 9]. Furthermore, the majority of patients with advanced GIST ultimately develop resistance to imatinib, which can either occur rapidly within 6 months of initiating therapy (primary resistance), or can appear with delay after 1 to more than 10 years on imatinib therapy. This delayed resistance usually occurs due to acquisition of secondary mutations in KIT or PDGFRA [10]. In the case of imatinib-resistant KIT-mutant GIST, these mutations cluster in the ATP-binding pocket (encoded by exons 13 and 14), and the activation loop (encoded by exons 17 and 18) of the kinase domain, and occur almost exclusively in the same gene and allele as the primary oncogenic driver mutation [10‐13].

Sunitinib is a multi-targeted oral inhibitor of KIT, PDGFRs, vascular endothelial growth factor (VEGF) receptors (VEGFRs), and several other receptor tyrosine kinases [14‐17]. It has shown clinically meaningful efficacy in phase I–III trials in imatinib-resistant or -intolerant patients with advanced GIST [18‐21], and continues to be used worldwide after imatinib in this patient setting. However, as is the case with imatinib, the clinical effectiveness of sunitinib is influenced by mutations in the KIT and PDGFRA genes. Findings from several small studies indicate that endpoints such as PFS and overall survival (OS) are significantly longer for patients with primary (pre-imatinib) KIT exon 9 mutations compared with those with KIT exon 11 mutations in both Caucasian [22, 23] and, more recently, Asian populations [24]. Secondary mutation status may also have a prognostic role in sunitinib therapy success [22, 25‐27], with data from small numbers of patients suggesting that mutation in exons 17 or 18 could confer some degree of resistance to the drug.

In the current study (Study 1199), we retrospectively examined correlations between clinical outcomes and KIT/PDGFRA mutational status in a subset of imatinib-resistant or -intolerant patients with GIST participating in a worldwide, open-label treatment-use study (Study 1036) [28].

Although effective in the vast majority of patients, the eventual evolution of resistance to imatinib is common in patients with GIST, with resistance observed in more than 80 % of evaluable patients during long-term follow-up in a phase III trial [30]. Sunitinib, a multi-targeted inhibitor of KIT and other receptor tyrosine kinases, is an important therapy for patients with GIST who become resistant to, or are intolerant of, imatinib. This non-interventional retrospective analysis (Study 1199) provided further evidence that imatinib-resistant or -intolerant patients with GIST experience clinical benefit from sunitinib treatment, regardless of the mutational status of their tumor. No mutational subsets of patients were found in the current study in which the drug was inactive, although this retrospective analysis had limited ability to assess very rare mutational subtypes or impact of various mutations in PDGFRA.

Clinical benefit associated with sunitinib-induced control of GIST is thought to be influenced by KIT mutational status [22, 24‐26, 31], and identifying those patients who are most likely to benefit from sunitinib treatment is desirable for both patients and clinicians. The current study aimed to correlate KIT mutational status data with clinical outcome in sunitinib-treated patients with imatinib-resistant or -intolerant GIST. The primary analysis revealed that individuals with a primary KIT exon 9 mutation in their tumor achieved better clinical outcomes during treatment with sunitinib than those with a primary KIT exon 11 mutation, across all three efficacy measures (PFS, OS, and ORR). Patients with KIT exon 9 mutations experienced a 41 % reduction in risk of progression, a 45 % reduction in the risk of death, and ORR that was three times higher, compared to those with primary KIT mutations in exon 11.

The observation that patients with GIST with a primary KIT mutation in exon 9 present with better outcomes following sunitinib treatment compared with those with a primary KIT mutation in exon 11 is consistent with previous studies in both Caucasian [22, 23] and Asian [24] populations. However, these studies involved relatively small patient sets of less than 100 subjects, resulting in low numbers of individuals within the different mutation subgroups. In contrast, the present study utilized data from a much larger cohort of 230 patients, including 42 harboring KIT exon 9 mutations and 143 with exon 11 mutations. The favorable outcomes in GIST with primary KIT mutations in exon 9 treated with sunitinib are consistent with in-vitro data, demonstrating greater potency of sunitinib over imatinib against exon 9 mutant KIT, and similar potency of each drug against exon 11 mutant KIT [22]. This observation could be due to the differential effect that mutation within each site has upon KIT receptor structure [32, 33].

Despite the non-randomized patient selection for this retrospective analysis, the baseline demographic and disease characteristics were similar to those observed in the parent Study 1036, which enrolled over 1000 patients with GIST from centers worldwide [28]. In addition, differences in dosing were unlikely to have impacted the findings. Previously reported post-hoc analyses of Study 1036 found that patients who received sunitinib on an alternative dosing schedule versus those who received only the initial dosing schedule had prolonged treatment, which may have led to improved outcomes, including prolonged TTP and OS [28]. However, among the 230 patients in the current study, 108 (47 %) had a dose reduction, similar to the number of patients in the parent study (43 %). Furthermore, the numbers of patients with dose reductions in the exon 9 and exon 11 subgroups in this study were comparable (both 48 %). Therefore, the results from the current study are likely to be broadly representative of the usual population that clinicians will see in everyday practice. In this respect, it is noteworthy that the distribution of primary KIT and PDGFRA mutations in our study was consistent with previous studies among patients with GIST [1, 8, 22]. Overall, 86 % of participants in our analysis had a primary mutation in KIT and 5 % had a primary mutation in PDGFRA.

Other secondary mutations may also influence response to sunitinib [22, 25‐27]. Data in small numbers of patients indicate that mutations in exons 17 and 18 may confer some degree of resistance to the drug. Unfortunately, information on secondary and tertiary mutation status of the patients in this study was not analyzable due to the limited availability of data. This was because, given the retrospective nature of this analysis, in some cases, only one biopsy was taken for each patient and also because biopsy collection timings varied between patients. Some biopsies were collected before beginning first-line treatment with imatinib (pre-imatinib, n = 148), some during or after completion of first-line treatment with imatinib, but before beginning treatment with sunitinib (post-imatinib/pre-sunitinib; n = 68), and some after the beginning or after completion of treatment with sunitinib (post-sunitinib; n = 24). This represents a limitation of this study. It should also be noted that only a subset of patients in the treatment-use study (Study 1036) were included in this correlation study; thus, this selected group of patients may not be fully representative of the pool of patients with secondary mutations. Finally, it should be noted that different mutational subtypes of KIT exon 9 and 11 may have a differential impact on treatment outcome (e.g. gastric GISTs with exon 11 deletions are more aggressive than those with substitutions) [34]; however, due to the limited number of patients, this level of analysis could not be performed in the current study.

Combined with the existing evidence, our data suggest that obtaining information on KIT mutations from patients before the start of treatment would allow clinicians to predict who are most likely to experience resistance to primary imatinib therapy, to evaluate which patients would benefit the most from sunitinib therapy, and also to aid in our understanding of why particular patients respond better than others. The data also support stratification by mutational status in future trials comparing sunitinib and novel agents. However, extensive intra- and inter-lesional heterogeneity of resistance mutations in patients with clinically progressing GIST is apparent, with up to five different secondary mutations observed in different metastases and up to two in the same metastasis in one study [35]. As a result of this, the information that can be generated from mutational analysis of a discrete, single tumor biopsy at the time of progression may confound subsequent treatment decisions. In the future, a meta-analysis of studies will be worthwhile to study the influence of rare mutations on outcomes in patients treated with sunitinib, and next-generation sequencing may provide more information on predominant and minor mutations that influence the efficacy of sunitinib and other agents. In addition, it must be remembered that mutational status is not the only prognostic factor that influences the clinical outcome of patients with GIST on receptor tyrosine kinase therapy, with initial low tumor volume, female gender, and CD34 positivity predicting higher PFS in a recent study considering patients treated with imatinib [36]. There is also evidence that exon 9-mutated GIST metastasizes significantly more often to the peritoneum than to the liver and that exon 9 mutations per se may not have prognostic relevance [37]; however, we do not have the level of data required to test a possible correlation of primary KIT mutation with metastasis status and location. Another important element of the multiple mechanisms of action of sunitinib as it pertains to GIST tumor biology is the complexity of the angiogenesis process. Expression of VEGF (a highly pro-angiogenic ligand of VEGFR2, which is another target of sunitinib but not of imatinib) has been shown to be higher in wild-type GISTs than in KIT-mutant GIST [38], and little is known about the angiogenic status at the time of progression on imatinib, which is likely to play a role in the mechanisms of resistance, as with many other targeted therapies. Finally, a recently reported study of theranostic biomarkers that identified potential therapies beyond tyrosine kinase inhibitors for GIST, including various cytotoxics and non-KIT/PDGFRA targeted therapies, underscores the heterogeneous nature of GIST [39].

In summary, this large retrospective study provides a robust analysis of the influence of KIT mutational status on clinical outcomes with sunitinib in patients with advanced GIST following failure of imatinib due to resistance or intolerance. The study also confirms the effectiveness of sunitinib as a post-imatinib therapy in patients, regardless of the mutational status of their tumor. It also confirms differential activity in KIT exon 9 versus exon 11 patients and adds to the limited data available on sunitinib activity in patients with other GIST mutations or SDH-deficient (“KIT/PDGFRA wild-type”) tumors. These data should give clinicians increased confidence in the effectiveness of sunitinib in all of these particular GIST patient subsets.