Strong Support for Not Interrupting Imatinib Treatment in Advanced GIST

Patients with advanced non-progressing gastrointestinal stromal tumors (GIST) who discontinued imatinib had more rapid progression, faster development of resistance, and worse overall survival (OS), a small randomized trial showed.

In patients randomized to discontinue treatment after 1 year, median progression-free survival (PFS) was just 6.1 months, as compared with 27.8 months for those who continued imatinib. And in randomizations (to discontinuation or continuous therapy) for patients with at least stable disease after 3 or 5 years of treatment, median PFS also significantly and substantially favored the patients who continued imatinib. Time to resistance was shorter at all time points for patients who discontinued treatment, including after the 1-year randomization (28.7 vs 90.6 months), but reached statistical significance at the 3-year randomization.

Analysis of OS showed advantages favoring treatment continuation at all time points, achieving significance in the 3-year randomization, reported Jean-Yves Blay, MD, of Leon Berard Center in Lyon, France, and co-authors in Lancet Oncology.

“In patients with advanced GIST, imatinib treatment should be continued without interruption until progression or intolerance,” the researchers wrote. “Because faster resistance to this tyrosine kinase inhibitor (TKI) emerged in the long term for patients with GIST in whom treatment was interrupted, similar studies should be conducted in patients with other cancers with activated mutated kinases treated with TKIs, and treatment interruptions in such patients should be proposed with caution and evaluated prospectively.”

The study adds to existing evidence that imatinib treatment for advanced GIST should continue without interruption, said the authors of an accompanying commentary.

“Patients with continued response and low-volume disease after 3 years might need less frequent imaging if they remain on imatinib, given the low rate of progressive disease and prolonged progression-free survival,” noted Ryan Denu, MD, PhD, and Neeta Somaiah, MD, of the University of Texas MD Anderson Cancer Center in Houston.

“There might also be a small patient population in which discontinuation is required due to clinically significant side effects that cannot be managed by dose reduction,” they continued. “Whether close monitoring in those patients or switching to an alternate tyrosine kinase inhibitor would be preferred is not known.”

The mechanisms underlying the shorter time to resistance after imatinib discontinuation remains open to conjecture, Denu and Somaiah pointed out. One theory posits that discontinuation “unleashes a burst of tumor cell proliferation” that exacerbates genomic and chromosomal instability, fueling tumor evolution and development. The theory might also explain why the phenomenon is not so pronounced in patients with localized GIST, wherein imatinib discontinuation after 2 years was not associated with rapid development of resistance or worse survival.

Imatinib remains the first-line standard for advanced GIST with imatinib-sensitive mutations. Whether treatment interruption affects resistance to imatinib or survival remains unclear, Blay and colleagues noted. They investigated the issue in the open-label BFR14 randomized trial that compared outcomes with uninterrupted treatment versus discontinuation at 1, 3, and 5 years, conducted at 17 cancer centers in France.

The study began with 102 patients with advanced GIST, all of whom received imatinib for 1 year. At that point, the 58 patients who attained stable disease or better response were randomized to stop treatment or continue. For the 3-year randomization, 50 patients with at least stable disease after 3 years of imatinib were randomized to continue treatment or discontinue. At 5 years, 27 patients with at least stable disease were randomized to continue or discontinue treatment. Patients assigned to the continuous arms with at least stable disease could be eligible for later randomizations.

The primary endpoint was PFS after 1, 3, and 5 years of imatinib, calculated from randomization to disease progression or death from any cause or to last follow-up. Secondary endpoints included OS and time to imatinib resistance.

The primary analysis showed that imatinib continuation was associated with significantly better PFS in the 1-year (HR 0.36, 95% CI 0.20-0.64, P=0.0003), 3-year (7 vs 67 months; HR 0.15, 95% CI 0.07-0.32, P<0.0001), and 5-year (12 months vs not reached; HR 0.13, 95% CI 0.03-0.58, P=0.0016) randomizations.

Median time to imatinib resistance favored uninterrupted treatment after 1 year, after 3 years (66.2 vs 127.3 months; HR 0.35, 95% CI 0.17-0.72, P=0.0028), and after 5 years (58.6 months vs not reached; HR 0.24, 95% CI 0.05-1.12).

Median OS associated with treatment interruption versus continuation was 56 vs 105 months after the 1-year randomization (a nonsignificant finding), 104 vs 134 months after the 3-year randomization (HR 0.40, 95% CI 0.20-0.82, P=0.0096), and not reached versus 110.4 months after the 5-year randomization (also nonsignificant).

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