HOW MANY

A total of 946 patients at 56 centers in 13 countries in Europe and Australia/New Zealand/Singapore took part in this trial. The study was open for enrollment from February 2001 till February 2002 and constitutes one of the first large trials of Imatinib (Glivec^®/Gleevec^®) in GIST.

STUDY DESIGN:

All participating patients were randomly divided into two groups: 473 patients were treated with Imatinib 400mg once daily, 473 patients were treated with imatinib 400 mg twice daily (total dose/day: 800 mg).

The two groups were evenly balanced on the basis of demographic and clinical characteristics of the patients. The majority of patients (72%) had received prior surgery (85 %), chemotherapy (33 %) and/or radiotherapy (7 %) for advanced GIST.
In both arms, treatment was given until disease progression, discontinuation due to unacceptable side effects (toxicity) or patient refusal. All patients were followed up until death from any cause or withdrawal of consent. In case of disease progression in a patient allocated to 400 mg once daily, the patient was allowed to crossover to 400 mg twice daily (dose escalation).

RESULTS

• How long will patients continue to respond to the therapy until their disease progresses (so called “progression-free survival”)?
• Will the higher dose of imatinib (400 mg twice daily) show a better overall survival (which was defined as the time from trial inclusion to date of death) than the lower dose (400 mg once daily)?
• How many patients will respond to each dose (response rate)?
• What are the side-effects in both groups and how intensive are they?

The following results were observed and published in 2017:

• Progression-free survival was 1.7 years (average) for treatment with 400 mg Imatinib once daily and 2.0 years for the higher dose of Imatinib (400 mg twice daily)
• Overall survival was 3.9 years in both treatment arms (average).

  

• In the lower dose group (400 mg once daily), 33 patients achieved a complete response, 208 a partial response. In the higher dose group (800 mg twice daily), 32 patients had complete response, 236 had partial response.

  

• The estimated 10-year progression-free survival was 9.5 % and 9.2 % for the 400 mg and 800 mg, respectively, and the estimated 10-year overall survival was 19.4 % and 21.5 %.

  

• Furthermore, the study found that general good health of the patient (performance status), prior chemotherapy, diameter of longest lesion and KIT mutation are relevant for progression-free survival, whereas age, status of general health, prior surgery, radiotherapy or chemotherapy as well as diameter of longest lesion and KIT mutation are relevant for survival.
• The trial also confirms that the KIT mutation status is predictive for progression-free survival, however, not for overall survival. Patients with a KIT exon 9 mutation significantly benefit from treatment with imatinib 400 mg twice daily.
• Patients with a KIT exon 11 mutation are more likely to respond than KIT exon 9 mutations, wild type or other.

CONCLUSION

This trial was initiated not long after imatinib became available for the treatment of GIST approximately 15 years ago. Little was known about GIST and the activity and potential of imatinib at the time.

These 10-year data show today that there is no difference in outcome (progression-free survival or overall survival) between the two doses of Imatinib. However, it confirms that patients with KIT exon 9 mutation benefit from starting on the higher dose of imatinib and that a higher dose is also beneficial for patients progressing under 400 mg imatinib once daily. It has to be noted though, that given the limited knowledge at initiation of this study, mutational analysis wasn’t carried out for all patients. Study investigators resume that the prognosis of advanced GIST patients starting imatinib today might be better overall due to improved and deeper knowledge about GIST. The publication of this study can be viewed here.

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