Adjuvant imatinib for GIST: duration likely matters

No effective systemic treatment was available for advanced gastrointestinal stromal tumour (GIST) until the introduction of tyrosine kinase inhibitor (TKI) imatinib at beginning millennium, with a median patient survival time just 10 to 20 months.1DeMatteo R.P. Lewis J.J. Leung D. Mudan S.S. Woodruff J.M. Brennan M.F. Two hundred tumors: recurrence patterns and prognostic factors survival.Ann Surg. 2000; 231: 51-88Crossref PubMed Scopus (2099) Google Scholar Imatinib first developed chronic myeloid leukaemia, but it also inhibited aberrant gene products KIT PDGFRA that are considered main drivers most GISTs. After GIST years ago leading remarkable response,2Joensuu H. Roberts P.J. Sarlomo-Rikala M. et al.Effect STI571 in metastatic tumor.N Engl J Med. 2001; 344: 1052-1056Crossref (1795) multicentre trials confirmed efficacy about 85% patients GIST.3Demetri G.D. von Mehren Blanke C.D. al.Efficacy safety mesylate tumors.N 2002; 347: 472-480Crossref (3603) Scholar,4Casali P.G. Zalcberg J. Le Cesne A. al.Ten-year progression-free overall unresectable or GI long-term analysis European Organisation Research Treatment Cancer, Italian Sarcoma Group, Australasian group intergroup phase III randomized trial on two dose levels.J Clin Oncol. 2017; 35: 1713-1720PubMed became useful TKI solid cancer role model new era small molecule targeted drugs. Many GISTs recur despite macroscopically complete surgery, often metastases peritoneum and/or liver. With astonishingly good GIST, logical initiate evaluate adjuvant imatinib. Three such have now been carried out, each investigating standard oral daily 400 mg. The US American College Surgeons Oncology Group (ACOSOG) Z9001, placebo-controlled study evaluating 1 year after surgery whose were ≥3 cm size.5Dematteo Ballman K.V. Antonescu C.R. al.Adjuvant resection localised, primary tumor: randomised, double-blind, trial.Lancet. 2009; 373: 1097-1104Abstract Full Text PDF (998) found improve recurrence-free (RFS), not (OS), possibly because responded well recurrence. later both open-label studies. Scandinavian (SSG)XVIII/German (AIO) compared 3 imatinib, including only high estimated risk according modified National Institutes Health (NIH) criteria.6Joensuu Vehtari Riihimäki al.Risk tumor surgery: an pooled population-based cohorts.Lancet 2012; 13: 265-274Abstract (572) follow-up, treated 3-year had longer RFS, they survived substantially statistically significantly than (10-year OS, 79% versus 65%, respectively) hazard ratio (HR) 0.55 [95% confidence interval (CI), 0.37-0.83] OS between groups intention-to-treat population. An even lower HR 0.50 death observed ‘true population’, when few who did central pathology review those date entry excluded.7Joensuu Eriksson Sundby Hall K. al.Survival outcomes associated vs high-risk clinical 10-year follow-up.JAMA 2020; 6: 1241-1246Crossref (30) final results third trial, EORTC/Intergroup reported Annals follow-up 9.1 years.8Casali Poveda Velasco al.Final as localized tumors from EORTC Soft Tissue Bone (STBSG), Gastro-Intestinal Trials (AGITG), UNICANCER, French (FSG), (ISG), Spanish Sarcomas (GEIS).Ann 2021; 32: 533-541Abstract (6) accrued 908 either intermediate randomly assigned : receive 2 control without treatment. endpoint initially planned interim trial9Casali al.Time definitive failure adjuvant: Cancer collaboration Sarcomas.J 2015; 33: 4276-4283Crossref (94) seemed apparent keeping would lead unreasonably long duration trial. changed ‘imatinib failure-free survival’ (IFFS), estimate drug resistance, defined randomization switching another any during following period. idea assess which strategy prolonged resistance most, comparing starting immediately Adjuvant improved neither IFFS [HR 0.87, 95.7% CI (0.65; 1.15)] nor 0.88, 95% 1.21)], RFS 0.71, (0.57; 0.89)] observation group. improvement mostly temporary, 5-year rates favoured (70% 63%), little difference (62.5% 61%). How do we interpret these findings light more favourable SSGXVIII/AIO where reduced deaths much 50% 1-year suggesting can be highly efficacious? authors write “may give some benefit run …. limited”. One obvious is administration SSGXVIII/AIO. may simply too short demonstrate full impact considering confounding effect substantial overtly recurrent GIST. Patient selection likely great importance since all harbour mutations confer exon 18 mutation D842V.10Cassier P.A. Fumagalli E. Rutkowski P. al.Outcome platelet-derived growth factor receptor alpha-mutated era.Clin Res. 18: 4458-4464Crossref (118) Importantly, over half intermediate-risk rarely low-risk majority known cured by alone6Joensuu are, therefore, unlikely Not surprisingly, derived no 2-year subset EORTC/intergroup is, other hand, considerable interest. In line data, there non-significant trend favour arm patients, although criteria differed somewhat used trial.7Joensuu Early discontinuation diluted Although mg/day usually tolerated possibility reduce toxicity, 21% discontinued reasons death, due toxicity. What suggested trials, IFFS? suggestion use IFFS-like endpoints seems innovative idea, worthy further evaluation agent first-line same. re-starting investigational needs guided detail protocol start, case purpose increase cure rate prolong decreasing quality life, merely always justify absence prolongation, though approved based ACOSOG Z9001 However, robust IFFS, data selected one key out conclusion, compatible confirm Taken together, three studies suggest careful critical enough needed. At present, remains care recurrence, mutational status suggests sensitivity Evaluation greater 3-year' priority, currently accruing (NCT02413736 NCT02260505), 5 years' up 6 treatment, respectively.