Additional 3 Years of Adjuvant Imatinib Maintenance Reduces Recurrence Risk in High-Risk GIST

Jean-Yves Blay, MD, PhD

Extending the duration of adjuvant imatinib (Gleevec) post-resection from the standard 3 years to 6 years conferred a significant reduction in the risk of recurrence or death without increasing the risk of developing resistance to the agent in patients with gastrointestinal stromal tumors (GIST) at a high risk of recurrence, according to data from the randomized phase 3 IMADGIST study (NCT02260505) presented during the ESMO Virtual Plenary: May 2024.¹

Among those who received 6 years of imatinib maintenance therapy, the 3-year disease-free survival (DFS) rate was 87% (95% CI, 76%-93%) vs 55% (95% CI, 42%-67%) in patients with just 3 years of imatinib treatment (HR, 0.40; 95% CI, 0.20-0.67; P = .008).

“[An] important observation here is that the patients who discontinued imatinib after 3 years had a median [DFS] after treatment interruption that was close to 5 years; [however], the majority of patients did progress or died following treatment interruption after 3 years. You can also see that [DFS in] the prolongation arm was significantly superior [to that of the interruption arm],” presenting author Jean-Yves Blay, MD, PhD, a professor of medicine at the University Claude Bernard and general director of the Centre Léon Bérard at the Comprehensive Cancer Centre of Lyon, in France, explained in an oral presentation. “[Accordingly], results from the IMADGIST trial support a 6-year duration of adjuvant imatinib for [patients with] high-risk GISTs.”

In patients with a risk of relapse between 35% to 70%, the DFS rate was superior in those treated with 6 years of imatinib vs 3 years of the drug (HR, 0.08; 95% CI, 0.01-0.61; P = .0016). Patients with a risk of relapse higher than 70% in the 6-year imatinib arm appeared to have numerically but not statistically superior DFS vs those in the 3-year imatinib arm (HR, 0.68; 95% CI, 0.34-1.34; P = .2581).

When looking at DFS in the subgroup of patients with a risk of relapse of greater than 70%, with or without rupture, Blay said: “This actually describes a situation that is a bit more complex than what we anticipated. You have a look at the split of the subgroup at a high risk of relapse with or without rupture and you can see that patients without rupture who are at a higher risk of relapse did derive a significant benefit [with] prolongation of treatment, whereas those with rupture [at the time of surgery and a] risk of relapse beyond 70% had a less significant DFS [benefit with 6- vs 3- year imatinib. We concluded that] the benefit [with 6-year imatinib] is observed for all patients except those with tumor rupture at the time of surgery.”

Background

Administration of adjuvant imatinib for 3 years is indicated after complete resection of primary, localized, KIT-positive GIST at high risk of recurrence. However, a large proportion of patients in this population relapse after the completion of adjuvant imatinib. It is not known whether a more prolonged treatment duration with adjuvant imatinib would benefit these patients.

“The question of the study was whether a more prolonged duration of adjuvant imatinib would be useful,” Blay stated during the presentation. “That was addressed by prolonging the duration of treatment beyond 3 years in patients reaching 3 years [of treatment] to check whether this additional duration of treatment would reduce the risk of [GIST] recurrence and ultimately improve overall survival [OS].”

About the Trial: Eligibility Criteria, Treatment, Objectives

The open-label, multicenter, 2-arm IMADGIST study^1,2 enrolled patients 18 years of age or older with a histologically confirmed diagnosis of localized GIST with documented KIT positivity by polyclonal DAKO antibody staining and documented macroscopically complete R0 or R1 resection of the primary GIST lesion. Treatment with adjuvant imatinib must have been initiated immediately after resection and maintained for 36 months.

Other key eligibility criteria included a 25% or higher risk of tumor recurrence as per the National Comprehensive Cancer Network (NCCN) Task Force on GIST risk classification, an ECOG performance status between 0 and 2, normal organ and bone marrow function at baseline, and no progressive disease. Patients harboring D842V mutations in PDGFRA were excluded from the study.

Once enrolled, patients were stratified by study site and their risk of GIST recurrence (35% to 70% vs above 70%). Patients randomly assigned to arm 1 continued treatment with adjuvant oral imatinib at the last dose routinely taken by the patient prior to randomization (300 or 400 mg per day) for 3 more years. Those assigned to arm 2 discontinued imatinib treatment according to standard practice. Reintroduction of imatinib was allowed in arm B upon disease progression.

The primary end point of the trial was DFS, and key secondary end points included OS, time to secondary imatinib resistance (TTIR), overall response rate after imatinib reintroduction, safety and tolerability, and quality of life.

A Deep Dive Into the Analysis

“Our statistical analysis was conducted with this hypothesis: to detect the hazard ratio under 0.462, corresponding to a 15% improvement in the 3-year DFS rate for the imatinib discontinuation arm compared with the imatinib maintenance arm,” Blay explained. Both the accrual period and follow-up period for the current analysis were 3 years, and 33 relapses were required to detect the target difference with 80% power.

Of the 136 patients enrolled in the study, 71 were assigned to arm 1 and 65 to arm 2.1

The median age of patients was 62 years (range, 25-84) in arm 1 and 63 years (range, 25-90) in arm 2. The majority of patients were male (60.6%) in arm 1 and female (61.5%) in arm 2. In both arms, most patients had a tumor size of greater than 10 cm (52.1% in arm 1; 47.7% in arm 2), and greater than 5 mitoses per 50 high-power fields (64.8%; 73.8%), and a risk of relapse higher than 70% (47.9%; 56.9%). Ruptures occurred in 9% (12,7) and 10% (15,4) of patients in arms 1 and 2, respectively. Most tumors were located in the small bowel (43.1%; 50.7%) or were gastric (50.7%; 43.1%).

“Not surprisingly, the majority of [KIT] mutations were located on exon 11. Among these, most mutations were deletions of codon 557/558. There were also mutations in exon 9, 13, and 17. These were primary mutations,” Blay clarified, adding that, “More rarely, there were mutations in PDGFRA.” In arm 1, 2 patients harbored respective PDGFRA exon 12 and exon 18 mutations. Two patients in arm 2 expressed PDGFRA mutations in exon 14 and exon 18, respectively.

In arm 1, the initial dose of imatinib maintenance at randomization was 400 mg per day in 88.7% of patients and 300 mg per day in 11.3% of patients. Over half of the patients (59.2%) were exposed to imatinib 3 years following randomization, with 9.9% undergoing 1 or more temporary dose interruptions and 2.8% undergoing 1 or more dose reductions. Among those who had less than 3 years of imatinib exposure post-randomization (40.8%), the follow-up period was less than 3 years in 16.9% of patients, and 11.3% experienced disease progression during this period. Reasons for early termination included toxicity (5.6%), investigator decision (2.8%), or patient decision (4.2%).

Additional Data

Secondary end points were not mature at the time of analysis. Current data showed that both TTIR and OS rates were not significantly different between the 3- and 6-year arms. Kaplan-Meir estimates for TTIR were 0.96 (95% CI, 0.86-0.99) and 0.93 (95% CI, 0.83-0.97) in the 3- and 6-year arms, respectively. For OS, these ratios were 0.95 (95% CI, 0.85-0.99) with imatinib interruption and 0.97 (95% CI, 0.87-0.99) with imatinib maintenance. Blay noted that only 7 OS events were observed across both arms at the 36-month time point and that additional follow-up is needed.

“The risk of developing resistance to imatinib was not observed to increase following the prolonged duration of 6 years, but this requires additional follow-up,” Blay stated. “The same is true for OS.”

In the 3-year arm, 6 progression-free survival (PFS) events were reported in patients who were reintroduced to imatinib following relapse (n = 24; Kaplan-Meier estimate, 0.70; 95% CI, 0.37-0.88). Blay stated that the median PFS in the group of patients who reinstated imatinib after progression was 14 months, adding that “This is very consistent with what is being reported in the first-line setting.”

Further subgroup analysis showed that all patients derived benefit from the prolongation of imatinib treatment. Blay said “We already spoke of the absence of an obvious benefit for patients with tumor rupture at initial diagnosis. This is also true for patients with [KIT] exon 9 mutations. Please note that this is a very small group of patients, and we cannot [draw conclusions] in a situation where the optimal dose of imatinib in [patients with KIT] exon 9 [mutations] has been recently investigated in retrospective studies.”

Safety Findings

Investigators compared the adverse effect (AE) profile of patients continuing imatinib with those who did not. The most common any-grade AEs observed were muscle spasms (51% in arm 1; 22% in arm 2), diarrhea (44%; 23%), asthenia (30%; 17%), fatigue (21%; 22%), abdominal pain (21%; 11%), eyelid edema (20%; 3%), myalgia (16%; 8%), nausea (14%; 15%), constipation (13%; 14%), vomiting (13%; 8%), anemia (9%; 11%), arthralgia (6%; 11%), and back pain (4%; 12%). Grade 3 or higher muscle spasms, anemia, and back pain were reported at low rates of 1% in the maintenance arm.

“Patients continuing imatinib have a significantly increased rate of muscle spasms and diarrhea; [conversely,] a patient with treatment interruption [experienced a] slight increase in arthralgia and back pain consistent with… imatinib withdrawal syndrome. The difference between the 2 arms in terms of serious AEs was not significant,” Blay concluded.

Disclosures: Dr Blay shared that the research was supported by academic grants from NETSARC+, INtERSARC+, PHRC, and EURACAN. Research support not related to this work was provided by PharmaMar, Bayer, Deciphera, Novartis, GlaxoSmithKline, AstraZeneca, MSD, Bristol Myers Squibb, and Roche. Blay disclosed receiving honoraria from PharmaMar, Deciphera, and Bayer, and serving as an advisory board member for Innate Pharma and Transgene.

References

1. Blay JY, Schiffler C, Bouche O, et al. A randomized study of 3 vs 6 years of adjuvant imatinib in patients with localized GIST at high risk of relapse. Presented at the 2024 European Society for Medical Oncology Virtual Plenary Meeting; May 9, 2024.
2. Efficiency of imatinib treatment maintenance or interruption after 3 Years of adjuvant treatment in patients with gastrointestinal stromal tumours (GIST) (ImadGist). ClinicalTrials.gov. Updated January 5, 2024. Accessed May 9, 2024. https://clinicaltrials.gov/study/NCT02260505