Basis for Treatment With Imatinib(Drug information on imatinib)
rosine kinase (TK) inhibitor that blocks KIT- or PDGFR-alpha polypeptide (PDGFRA)-mediated signaling. The incorporation of this drug into early GIST trials completely changed the treatment for this disease. Imatinib obstructs signaling by binding to the ATP pocket required for phosphorylation and activation of the TK receptor. Imatinib was first approved for the treatment of chronic myelogenous leukemia,[19,20] in which an aberrant TK (bcr-ABL) results from molecular rearrangement. The finding that mutational activation of KIT stimulates growth of GIST cancer cells, coupled with imatinib’s ability to preclinically inhibit KIT in GIST cell lines, led to the development of several clinical investigations. These started with a successful case report, which was quickly followed by phase II and III studies.
Van Oosterom and colleagues reported the results of a phase I trial that included patients with metastatic GIST, demonstrating that doses up to 400 mg twice a day were tolerable, with an outstanding 82% overall clinical benefit and a very acceptable toxicity profile. The most common side effects were periorbital edema (40%), peripheral edema (37.5%), fatigue (30%), skin rash (30%), and nausea/vomiting (25%). Myelosuppression was also seen occasionally.
Demetri and associates conducted a phase II trial randomizing 147 patients to receive imatinib at 400 or 600 mg daily. A total of 79 patients (53.7 %) had a partial response, 41 patients (27.9 %) had stable disease, and responses could not be evaluated in 7 patients (4.8%). No significant differences were seen in toxicity or response between the two doses. This group recently published the long-term results from this trial. In 71 months, 2 patients (1.4%) achieved a complete response and 98 (66.7%) had a partial response, for a total response rate of 68.1%. A total of 23 patients (15.6%) had prolonged stable disease for more than 1 year. The median duration of response was 29 months, and the median survival was 57 months for all patients. Overall, 46 patients (31% of the original cohort) were still taking imatinib at 5 years.
Phase III trials have been conducted to determine ideal treatment duration and optimal dose.[27,28] Most recently, important data from a meta-analysis of two large trials included two nearly identical randomized studies comparing 400 mg of daily imatinib to 800 mg daily for the treatment of incurable GIST. A total of 1,640 patients were included, with the analysis showing a small progression-free survival advantage for high-dose imatinib, but no overall survival advantage. Interestingly, the progression-free survival benefit derived solely from patients with exon 9 mutations.
Based on such data, the current standard imatinib regimen for metastatic GIST remains a daily dose of 400 mg, given continuously, except for exon 9 patients, who should quickly be dose-escalated to 800 mg daily (see below). The results yielded by the use of imatinib against GIST represented a dramatic paradigm shift away from ineffectual chemotherapy, and highlighted the potential of TK inhibitors as a treatment for solid cancers.
Tumor Genotype and Response to Therapy
Since GISTs commonly possess activating mutations in KIT or PDGFR, information about the influence of genetic subtype on the clinical response to imatinib has been of great interest. An early publication was based on the 127 patients enrolled in the phase II clinical study of imatinib detailed above. Archival pretreatment pathology specimens were obtained from those patients, sections were prepared from formalin-fixed, paraffin(Drug information on paraffin)-embedded pretreatment specimens trimmed to enrich for tumor cells. Polymerase chain reaction amplification of genomic DNA for KIT and PDGFRA was performed, and amplicons were analyzed for mutations. Mutation types were clearly correlated with clinical outcome. Activating mutations of KIT or PDGFRA were found in 112 (88.2%) and 6 (4.7%) patients, respectively. Most KIT mutations involved exon 9 (n = 23) or exon 11 (n = 85).
In patients with GISTs harboring exon 11 KIT mutations, the partial response rate was 83.5%, whereas patients with tumors containing an exon 9 KIT mutation had a partial response rate of 47.8% (P = .0006). No responses were observed in patients with PDGFR mutations or no detectable mutation of KIT. Patients whose tumors contained exon 11 KIT mutations had a longer event-free and overall survival than those whose tumors expressed exon 9 KIT mutations or had no detectable kinase mutation.[30,31]
Later published data confirmed the importance of genotype regarding the response rate and overall outcomes in GIST, but with different conclusions. In the European-Australasian phase III study, pretreatment tumor specimens from 377 patients were analyzed for mutations of KIT and PDGFRA (when KIT-negative). Activating KIT mutations were detected in 315 of 377 tumors (83.6%), including mutations of exon 11 in 248 (65.8%), exon 9 in 58 (15.4%), exon 13 in 6 (1.6%), and exon 17 in 3 (0.8%). PDGFRA genotyping performed for 62 tumors without activating KIT mutations identified PDGFRA mutants in 10 (16.1%), usually involving point mutations or deletions in exon 18.[32,33]
In the North American randomized phase III trial, KIT mutations were identified in 280 patients (86.4%) and PDGFRA mutations in 3 (0.9%). A total of 41 patients demonstrated no KIT or PDGFRA mutations. Clinical response to imatinib was related to tumor mutational status in both phase III studies. Response rates for patients with mutations on KIT exon 11 or exon 9, or without KIT and PDGFRA mutations were respectively 69%, 34%, and 25% in the European-Australasian study, and 67%, 40%, and 39% in the North American trial.
It is clear that the patients who achieve the best response rates with imatinib are those with exon 11 mutations. Those with exon 9 mutations may derive some benefit from higher initial imatinib doses, with an increased response rate and a possible benefit in overall survival. In addition, about one-third of patients with PDGFR mutations may respond to imatinib therapy.
Response Evaluation Criteria in Solid Tumors (RECIST) remains the most commonly used system to define objective responses in GIST. This standard measures only the longest diameter of the lesions, with a partial response being defined as a 30% decrease in the sum of the longest dimensions of the measurable tumors. Progressive disease is defined as a 20% increase in the tumor length. However, it is rapidly becoming evident that the RECIST criteria are inappropriate to follow GIST responses to the new TK inhibitors, which may induce an early decrease in tumor density, with size increase, followed only later by a slow regression in tumor size.
There has been great interest in evaluating the metabolism of tumors treated with imatinib and other TK inhibitors using 18F-fluorodeoxyglucose positron-emission tomography (FDG-PET). Early data have demonstrated that FDG-PET is very sensitive in detecting early responses, as quickly as after a single dose of treatment. In one small study, 17 patients with GIST received 400 mg/d of imatinib. An FDG-PET response was observed in 13 patients (11 complete responders and 2 partial responders). A subsequent computed tomography (CT) response by RECIST was confirmed in 10 of those 11 patients. FDG-PET–stable or progressive disease was observed in eight patients, none of whom achieved a subsequent response by conventional tomography. An FDG-PET response was also associated with a longer progression-free survival (92% vs 12% at 1 year, P = .00107). However, FDG-PET is still expensive and unavailable in many areas of the world, generating great interest in new tomography modalities that could yield similar results.
Recently, Choi and colleagues conducted a study to evaluate whether specific CT findings of GIST after imatinib treatment correlated with tumor responses by FDG-PET. A total of 40 patients with metastatic GIST treated with imatinib were evaluated with both imaging techniques, and a multivariate analysis was performed using tumor size and density (Hounsfield unit) on CT, and maximum standardized uptake value (SUV) on FDG-PET. A decrease in tumor size of more than 10% or a decrease in tumor density of more than 15% on CT had a sensitivity of 97% and a specificity of 100% in identifying FDG-PET responders vs 52% and 100% when RECIST criteria were used. Such data suggest that CT using the new Choi criteria is an excellent method of assesing treatment response in GIST, with a far lower cost than using FDG-PET.[39,40]
In modern oncology, the term adjuvant therapy usually applies to treatment given in addition to surgery, usually following resection, when all detectable disease has been removed. Considering the strong data supporting the use of imatinib as a treatment for metastatic GIST, the favorable safety profile associated with its use, and the high recurrence rate associated with this tumor even following complete resection, a strong theoretical basis existed for the investigation of imatinib after resection in patients with GIST.[41,42]
An early phase II trial assessed 107 patients with high-risk KIT-expressing resected primary GIST. These patients were treated with 1 year of imatinib, 400 mg/d, starting 2 months after surgical resection. Imatinib therapy was well tolerated in this patient population. After a median follow-up of 4 years, the 1-, 2-, and 3-year overall survival rates were 99%, 97%, and 97%, respectively. The 1-, 2-, and 3-year recurrence-free survival rates were 94%, 73%, and 61%, respectively.[43,44]
A Chinese group also evaluated adjuvant imatinib in a phase II study with similar results. In this trial, 51 patients were included in the intention-to-treat analysis and 43 patients (75.4%) finished at least 12 months of imatinib treatment. Tumor relapses or metastases were identified in two patients (3.92%) at 350 and 680 days postoperation. The median disease-free survival was 385 days. No serious adverse events were reported. The score in quality of life showed no statistically significant difference between the baseline and the follow-up visits.
Randomized trials have also been conducted in this setting. The American College of Surgeons Oncology Group (ACOSOG) evaluated the benefit of adjuvant therapy in patients following complete resection of intermediate- or high-risk GIST. Patients with tumors measuring 3 cm or greater were randomly assigned to 1 year of adjuvant imatinib at 400 mg daily or placebo. The only stratification criterion was tumor size (< 6 cm, 6–10 cm, > 10 cm). A planned interim analysis of 644 patients from 230 centers followed for a median of 14 months showed that patients who were randomized to treatment had significantly fewer recurrences (3% vs 17%). As expected, patients with a larger tumor at diagnosis achieved the best risk reduction with therapy in the subgroup analysis. A total of 38 recurrences occurred in the 158 patients with tumors larger than 10 cm—30 in the placebo arm and 8 in the imatinib arm (P < .001; hazard ratio [HR] = 0.19; CI = 0.09–0.41).
In the subgroup with intermediate-size tumors (6–10 cm), 217 patients were treated and 30 recurrences occurred, 21 in the placebo arm (P = .01; HR = 0.37; CI = 0.17–0.81). In the subgroup of those with tumors less than 6 cm in diameter only (n = 263), 15 recurrences were observed—4 in the imatinib recipients and 11 in the placebo recipients, with no statistically significant difference between these groups.
At the time the data were released, no survival difference was noted between patients treated with imatinib vs placebo. The toxicity profile was similar to that observed in other imatinib trials with the exception of a virtual absence of tumor bleeding. Additional trials will be necessary to address the value of longer durations of imatinib following complete surgical resection, as there were many late recurrences after imatinib was stopped. The European Organisation for Research and Treatment of Cancer (EORTC) is leading a phase III trial that randomizes patients to 2 years of adjuvant imatinib (400 mg) or placebo. Another European study by the Scandinavian Sarcoma Group (SSGXVIII) is evaluating the use of adjuvant imatinib for 1 or 3 years in 240 patients with high-risk GIST after resection.