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Adjuvant imatinib for GIST: duration likely matters

2021; Elsevier BV; Volume: 32; Issue: 4 Linguagem: Inglês

10.1016/j.annonc.2021.01.073

1569-8041

Mikael Eriksson, Heikki Joensuu,

Gastrointestinal disorders and treatments

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