Advanced GIST Study – many lives changed

An article by Professor John Zalcberg OAM

The impending closure of the Advanced GIST Study, a randomised phase III international study of imatinib in metastatic or locally advanced gastrointestinal stromal tumours (GIST), reflects a critical milestone in the management of this disease.   The AGITG was fortunate to be involved at the outset in this important study, which saw patients with incurable GIST benefit from access to a new drug which dramatically changed the lives of so many patients with no remaining treatment options.

The study, which was led by the European Organisation for Research & Treatment of Cancer (EORTC), opened in record time after first being discussed at the American Society of Clinical Oncology (ASCO) in the year 2000.   Protocol development occurred throughout the rest of the year in an environment where only few Australian patients were able to access imatinib by travelling overseas.   The trial was opened in February 2001 and our first patient was recruited at the Ashford Cancer Centre — the only site in the country with Ethics approval at the time.   That month the AGITG recruited four patients and the EORTC overall recruited three patients.   Our third patient was admitted to ICU at Ashford, such was the extent of disease in that patient’s case.   He walked out of hospital three weeks later on long-term imatinib.   The impact of this drug on patients was so much more dramatic than anything we had seen in GI cancer previously, with rapid improvement in symptoms to be followed shortly thereafter by improvement in PET scans and ultimately CT scans and of course, long-term survival.

Overall 946 patients were recruited to the study in 12 months from 13 countries. The AGITG recruited 116 patients from Australia, New Zealand and Singapore. Nearly 14 years after recruitment closed we still had 16 local study patients alive and in the follow up stage, all contributing data to the longer term outcomes of this study.

As clinicians, the prior experience with imatinib in phase I and II studies was such that none of us felt that a randomised trial against placebo was ethical and hence the study was designed as a comparison of two doses of imatinib (400mg vs 800mg), with cross-over allowed to the higher dose arm at the time of progression on the lower dose.

Much has been learned since the start of this important trial.   But most of all, this trial and the related North American study, changed the standard of care for patients with GIST.   Initially, we learned about a tumour that had previously been labelled as a leiomyosarcoma.   We learned about its cellular origins, the importance of drugs that target a driver mutation and indeed a founder mutation not only in GIST, but in cancer more generally.   We learnt about the predictive role of PET scans, the relevance of standard RECIST criteria for this disease, we learned about the toxicity of imatinib at standard and high doses.   We learned about the role of c-kit and PDGRA mutations and the relevance of these mutations in determining response.   We also learned about a new subgroup of tumours that phenotyped as a GIST but were rare sub-types – so called wild-type GIST.   Familial syndromes of GIST taught us more about the underlying mutations, but importantly they continued to remind us of the tragedy when such incurable diseases afflict families, even when effective drugs are available.

The study spawned second and third line treatments options although we have struggled to use these options to improve overall cure rates, as bringing these into the first-line settings has not been a successful strategy thus far. But it also led to an era of successful adjuvant studies which further improved outcomes for patients with a resected GIST.

We were also reminded of the complexities of reimbursement systems in Australia and the power of advocacy by the community in influencing Government decision-making.

We learned a lot as a co-operative group, benefiting enormously from the collegial approach within Australia, New Zealand and Singapore, the capacity to work with international groups in Europe and the importance of networking, most of all for our patients but also for clinicians working as a team, asking how do we do it better!

Clinical staff around Australia, New Zealand and Singapore and staff at the NHMRC Clinical Trials Centre have made an enormous contribution to this significant advance in the care of patients with GIST.   We all have the right to feel proud of a job well done.