BRF14 Data Demonstrate Long-Term Efficacy of Imatinib in Advanced GIST

With over 18 years of median follow-up, imatinib (Gleevec) was found to provide 20-year survival for over 10% of patients with advanced gastrointestinal stromal tumors (GIST), with higher rates of long-term survival observed in females, those with smaller primary tumors, and those with KIT exon 11 mutations, according to findings from the phase 3 BFR14 trial (NCT00367861). 1

The data, which were published in Annals of Oncology, showed that the median OS for all patients (n = 424) was 75.3 months (95% CI, 63.9-86.6), and the median GIST-specific survival was 83 months (95% CI, 70.2-97.7). Moreover, after imatinib initiation, 56% of patients were alive at 5 years, 33.9% at 10 years, 19.8% at 15 years, and 13.1% at 20 years.

Notably, those who achieved complete responses (CRs) to imatinib experienced a significantly superior median overall survival (OS) of 171.6 months vs those who experienced a partial response (PR) or stable disease (SD; 95% CI, 137.8-205.3; P < .001). Moreover, 14.9% of patients had surgical intervention for the resection of intraabdominal metastases and 9.2% of them achieved complete resection (R0). Those who achieved R0 experienced a median OS of 173.8 months (95% CI, 88.4-259.1), which was determined to be significantly superior to that of those achieving marginal or incomplete resections.

“This update of the BFR14 study provides important insights into the very long-term outcome of advanced GIST patients treated in the first years of imatinib availability,” Jean-Yves Blay, MD, PhD, Centre Léon Bérard & Université Claude Bernard Lyon 1 & Centre de Recherche en Cancérologie de Lyon, in Lyon, France, and colleagues, wrote in the paper. “A proportion of patients is alive at 20 years without progression. This proportion is larger in those patients achieving CR, with medical treatment and surgery. To determine whether some of these patients are cured will require an even longer follow-up.”

Breaking Down BFR14: Trial Design, Patients, Objectives

Imatinib continues to be the standard frontline treatment of patients with advanced GIST.1,2 However, very long-term outcomes of those with advanced disease who receive the agent are not well known.

The open-label, multicenter, randomized, phase 3 trial enrolled patients with metastatic or unresectable GIST who could have previously received chemotherapy. Patients were at least 18 years of age, had an ECOG performance status ranging from 0 to 3, and immunohistochemical documentation of KIT expression.

Participants received a daily dose of imatinib at 400 mg, which increased to 600 mg daily upon disease progression. After 1, 3, or 5 years of treatment, they were proposed for randomization to the STOP arm, which was imatinib interruption until disease progression by RECIST criteria and then reintroduction of the agent; or the CONT arm, which was imatinib continuation until disease progression or intolerance.

The primary end point was progression-free survival in 2 randomized groups of those with CR, PR, or SD by RECIST criteria after 1, 3, and 5 years of treatment with the drug. Secondary end points included OS, response rate following imatinib reinitiation in the STOP arm, time to treatment failure (TTIF), prognostic impact of known driver molecular alterations, and impact of surgery of metastases during treatment.

Of the total patients, 58.5% were male, half of patients had a performance status of 0 at the time that they started treatment with imatinib, and most patients had tumors located in the stomach (37.1%) and small bowel (44.1%). Additionally, the median size of the primary tumor was 50 mm (range, 5-245).

Additional Efficacy Data

The median TTIF was 42.6 months; the 10-, 15-, and 10-year rates of TTIF were 17.1%, 11.2%, and 6.1%, respectively. Better TTIF was noted in females, those with primary tumors smaller than 50 mm, those with a primary gastric site, performance status below 2, and those with tumors harboring KIT exon mutations.

Those with a CR to imatinib experienced a median TTIF of 90.6 months, which was found to be significantly superior to those who had a best response of PR or SD to treatment. Moreover, those with an R0 surgery status experienced a median TTIF (OS) of 73.3 months (95% CI, 53.1-93.5), which was determined to be significantly superior to those with marginal or incomplete resections.

Additionally, median survival after imatinib failed was 13.7 months (95% CI, 10.7-16.7); the 10-year survival rate was 6.3%, 15-year survival rate was 5.1%, and 20-year survival rate was 0%. Prognostic factors for survival that were identified for this subset included having primary tumors smaller than 50 mm, a performance status of 0, being younger than 62 years, and harboring KIT exon mutations.

Investigators also conducted a multivariate analysis of prognostic factors for OS, TTIF, and survival post-imatinib failure. They found that females and those with tumors harboring KIT exon 11 mutations had a better prognosis than those with small bowel primary, a performance status higher than 1 at the start of treatment, and those who were older. Primary tumor size was also noted as an independent adverse prognostic factor.

Independent adverse prognostic factors for TTIF included primary tumor size, performance status at start of treatment, female sex, and KIT exon 11 mutations. Independent favorable prognostic factors for survival post-imatinib failure were duration of imatinib treatment prior to failure, age, and primary tumor size.

Proposed Predictors for 15-Year Survival

To examine prognostic parameters linked with 15-year survival, investigators leveraged logistic regression; those significantly associated with this long-term survival in the univariate analysis were included in the model. Findings revealed that a continuous factor linked with survival at 15 years was younger age. Moreover, higher rates of 15-year survival were associated with female sex and KIT exon 11 mutations. Primary tumor size was identified as a continuous variable.

Key Takeaway

“While predictive tools developed from this study may be used to identify patients who are more likely to be long-term survivors earlier, further research should aim to expand on these findings with a focus on current populations and the integration of newer therapeutic agents to continue advancing the care of patients with GIST,” the study authors concluded.

References

1. Blay J-Y, Devin Q, Toulmonde M, et al. Twenty-year survival of advanced gastrointestinal stromal tumours treated with imatinib: exploratory long-term follow-up of the BFR14 trial. Ann Oncol. 2025;36(9):1035-1046. doi:10.1016/j.annonc.2025.05.535
2. Chan A. Imatinib remains standard of care in GIST with a ‘a long way to go.’ July 13, 2025. Accessed August 22, 2025. https://www.onclive.com/view/imatinib-remains-standard-of-care-in-gist-with-a-long-way-to-go-