Longer imatinib use confers survival benefit for GI stromal tumours

Three years of adjuvant imatinib treatment is superior in efficacy vs 1-year use in patients with gastrointestinal stromal tumours (GIST) at high risk of recurrence post-surgery, according to the secondary analysis of the SSGXVIII/AIO* trial.

“Imatinib remains the only approved tyrosine kinase inhibitor (TKI) for adjuvant treatment of GIST, [which has unfavourable prognostic features],” said the researchers. However, despite the improved survival outcomes, the median survival time is only 2–3 years. [J Clin Oncol 2018;36:136-143]

“[Our findings suggest that adjuvant imatinib in patients with] a high risk of recurrence despite macroscopically complete surgery is an attractive strategy for improving survival,” they stressed.

The intention-to-treat (ITT) cohort comprised 397 patients** (median age 61 years, 51 percent male) who were randomized 1:1 to receive imatinib 400 mg daily for either 1 or 3 years post-surgery. An efficacy subgroup was formed to exclude patients without GIST as per pathology review and those who had intra-abdominal metastases (on top of the primary tumour) removed at laparotomy (n=15 and 24, respectively). [JAMA Oncol 2020;doi:10.1001/jamaoncol.2020.2091]

In the ITT cohort, recurrence-free survival (RFS) rates were higher with the 3- vs the 1-year regimen, both at 5 (71 percent vs 53 percent) and 10 years (52 percent vs 42 percent; hazard ratio [HR], 0.66; p=0.003).

The longer regimen still outdid the shorter in terms of overall survival (OS), be it at 5 (92 percent vs 86 percent) or 10 years (79 percent vs 65 percent; HR, 0.55; p=0.004). “[This implies that about] 50 percent of deaths may be avoided during the first [decade] of follow up after surgery with longer adjuvant imatinib treatment,” explained the researchers.

Evaluation of the efficacy cohort reflected similar benefits with the 3- vs the 1-year regimen, both in terms of 10-year RFS (52 percent vs 44 percent; HR, 0.70; p=0.02) and OS (82 percent vs 67 percent; HR, 0.50; p=0.003).

The survival durations appear favourable compared with a study on first-line imatinib. [J Clin Oncol 2008;26:620-625] “[This suggests] that adjuvant imatinib may not markedly impair the efficacy of subsequent TKI treatments,” they said. However, this should be interpreted with caution owing to potential confounders. [Lancet 2013;381:295-302]

While evidence suggests that imatinib is cardiotoxic, [Nat Med 2006;12:908-916] both arms had a similarly low incidence of cardiac events (6 percent [1 year] vs 5 percent [3 years]). Secondary cancers were detected in 12 percent and 17 percent of patients in the respective 1- and 3-year arms, the most common being prostate cancer. No new safety signals were reported.

Too short, too low?

Despite the long follow up, the researchers noted that this appears “too short” to fully assess imatinib in the adjuvant setting. Another limitation is the dose, which may have been “too low” for patients with KIT exon 9 mutation. [Eur J Cancer 2006;42:1093-1103] “[Moreover,] the longitudinal imaging [used] may have resulted in early detection of recurrences, potentially leading to a lead time bias and slow emergence of gene mutations that confer drug resistance,” they added.

The initial*** SSGXVIII/AIO results have influenced guideline recommendations of the US NCCN^# and ESMO^## favouring a 3-year imatinib regimen for high-risk GIST. [JAMA 2012;307:1265-1272; J Clin Oncol 2016;34:244-250; J Clin Oncol 2015;33:4276-4283; Ann Oncol 2018;29:iv267] Studies on 5 or 6 years of adjuvant imatinib treatment are in progress to ascertain the efficacy of longer adjuvant imatinib treatment in this setting.