Systemic Therapy
Imatinib - Clinical Investigation
The US/Finland (B2222) trial was a phase 2 trial conducted at several US centers and in Finland. B2222 was a randomized, open-label study of Glivec® in patients with unresectable or metastatic malignant GISTs expressing KIT. The first patient was enrolled on July 6, 2000.1
The primary objective of the core study, which followed patients for up to 36 months, was to assess the clinical activity of Glivec in patients with unresectable or metastatic malignant GIST as judged by objective response rates.2 The objective of the extension trial, which allowed treatment for up to 4 additional years (7 years total), was to assess the long-term efficacy of Glivec measured by time to response, rate of duration of responses, time to treatment failure, and overall survival.3
The core study enrolled 147 patients with advanced GIST, who were randomized to receive 400 mg or 600 mg of Glivec once daily. Patients ranged from 18 to 83 years of age.1 The initial analysis, at a median follow-up of more than 9 months, documented that 54% of patients had achieved a partial response and 28% had maintained stable disease; there were no complete responses. Primary resistance or refractoriness to Glivec occurred in 14% of patients.
Data at 64 months
At a median follow-up of 64 months,3 1% of patients had achieved a complete response, 67% had achieved partial response, and 16% had maintained stable disease; these percentages reflect the fact that some patients who initially had maintained stable disease as best response achieved partial response with longer treatment (Table 1). Median time to response was 13 weeks, but 25% of patients responded after 6 months. Complete response was reported in 2 patients (1%). No significant difference in response rates was observed between the 2 dose groups. Median duration of response was 118 weeks (29.5 months).
Median overall survival for both dose groups was 57 months (Figure 1) (data on file, Novartis Pharmaceuticals). Best response was a clear predictor of survival (Figure 2). Median overall survival was 63 months for patients achieving a complete or partial response, but it had not been reached for patients achieving stable disease. Patients whose best response was progressive disease had a median survival of 8 months. Only 7 patients were classified with unknown and/or nonevaluable best response; their median survival was 144 weeks, but the value is not statistically reliable because of the small number of patients.
| 400 mg | 600 mg | All Doses | |
|---|---|---|---|
Best Response | N = 73 n (%) | N = 74 n (%) | N = 147 n (%) |
| Complete response Partial response Stable disease Progressive disease Not evaluable Unknown |
0 50 (68.5) 10 (13.7) 11 (15.1) 2 (2.7) 0 |
2 (2.7) 48 (64.9) 13 (17.6) 6 (8.1) 3 (4.1) 2 (2.7) |
2 (1.4) 98 (66.7) 23 (15.6) 17 (11.6) 5 (3.4) 2 (1.4) |
Figure 1 - Study B2222: overall survival by treatment at 64 months
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Study B2222: overall survival by treatment at 64 months (data on file, Novartis Pharmaceuticals). CI, confidence interval; LL, lower limit; N/A, not available; UL, upper limit.
Figure 2 - Study B2222: overall survival by best response at 64 months
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Study B2222: overall survival by best response at 64 months (data on file, Novartis Pharmaceuticals).
CI, confidence interval; CR, complete response; LL, lower limit; N/A, not available; PD, progressive disease; PR, partial response; SD, stable disease; UL, upper limit.
Median time to treatment failure (TTF) was 19 months for the overall patient population as well as both dose groups (95% CI, 16-25 months; hazard ratio, 0.840).4
Time to treatment failure was correlated with best response: 28-month median for patients with partial response versus 12 months for patients with stable disease; patients who failed to achieve stable disease, partial response, or complete response had a median TTF of less than 2 months.
The investigators drew several important conclusions from this study.3,5,6
- The efficacy of Glivec® in GIST has been demonstrated through a confirmed tumor response in 68% of the study patients; a total of 84% of patients received a clinical benefit (complete response + partial response + stable disease).
- Achieving confirmed stable disease is as important as achieving confirmed partial response in terms of overall survival. Survival rates for these groups of patients seem to be similar. The data are approaching maturity, with median survival now known for most patient groups. The most serious adverse events encountered with Glivec® in this patient population were
related to a low incidence of intratumoral and GI bleeds. However, the drug is well tolerated, both acutely and chronically, with a low incidence of severe adverse effects (Table 2). The safety profile and incidence matched those seen in studies with CML patients. - Glivec is the first small-molecule protein-tyrosine kinase inhibitor evaluated in a clinical setting and shown to be effective as a rationally targeted therapeutic modality against GIST.
| 400 mg | 600 mg | All Patients | |
|---|---|---|---|
| Grade 3/4 Adverse Event | N = 73(%) | N = 74(%) | N = 147(%) |
| Fluid retention |
6.8 |
12.2 |
9.5 |
| Abnormal pain |
12.3 |
5.4 |
8.8 |
| Any hemorrhage |
5.5 |
10.8 |
8.2 |
| Liver toxicity |
5.5 |
8.1 |
6.8 |
| Diarrhea |
2.7 |
6.8 |
4.8 |
| Nausea |
5.5 |
4.1 |
4.8 |
| Operations |
5.5 |
4.1 |
4.8 |
| Vomiting |
2.7 |
5.4 |
4.1 |
| Musculoskeketal pain | 5.5 | 1.4 | 3.4 |
*Based on final analysis of the STI B2222 core study (median follow-up of 41 months). Based on information from Blanke CD et al. 2006 Gastrointestinal Cancers Symposium; January 26-28,2006; San Francisco, Calif. Abstract 7.5
References:
1. Demetri GD, von Mehren M, Blanke CD, et al. Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N Engl J Med. 2002;347:472-480.
2. Glivec summary of product characteristics [SMPC]. Basel, Switzerland: Novartis Pharma AG; 2006.
3. Blanke C. Efficacy of imatinib mesylate in advanced gastrointestinal stromal tumor (GIST) patients (pts) according to tumor bulk. Presented at: 2007 Gastrointestinal Cancers Symposium; January 19-21, 2007; Orlando, Fla. Abstract 21.
4. Sandau K, Wehrle E. Clinical development. STI571/Glivec or Gleevec/imatinib mesylate. CSTI571B2222 and CSTI571B2222E1. East Hanover, NJ: Novartis Pharmaceuticals Inc; 2005:1-18.
5. Blanke CD, Joensuu H, Demetri GD, et al. Outcome of advanced gastrointestinal stromal tumor (GIST) patients treated with imatinib mesylate: four-year follow-up of a phase II randomized trial [abstract]. Presented at: 2006 Gastrointestinal Cancers Symposium; January 26-28, 2006; San Francisco, Calif. Abstract 7.
6. Blanke CD, Demetri G, von Mehren M, et al. Long-term follow-up of a phase II randomized trial in advanced gastrointestinal stromal tumor (GIST) patients (pts) treated with imatinib mesylate [abstract]. J Clin Oncol. 2006;24:526s. Abstract 9528.