Formal discussant of the PAZOGIST trial at the European Society for Medical Oncology (ESMO) 2014 Congress, Stefan Sleijfer, MD, PhD, of Erasmus MC Cancer Institute, Rotterdam, the Netherlands, said “The title of my talk is ‘Small Molecules: Greater Success,’ and we are not yet there.”
He agreed with Dr. Blay that pazopanib (Votrient) deserves further study in patients with advanced gastrointestinal stromal tumor (GIST) but suggested that these studies be conducted using a mutational-profile treatment approach, adjusting for changes in driver mutations with disease progression.
“The introduction of imatinib [Gleevec] was a miracle; median overall survival now exceeds 5 years, whereas before imatinib, it was 9 months. However, despite great success with this drug in first-line therapy, the vast majority of patients develop resistance. In the second- and third-line settings, response rates are lower and there is a need for novel therapies,” he noted.
The best design of future trials should be based on the mutational drivers at the time of progression or resistance. “The drivers of GIST at diagnosis are c-KIT or [platelet-derived growth factor receptor (PDGFR)-alpha]. With a different molecular background at progression than at diagnosis, it is unlikely that one drug will produce stabilization after imatinib failure,” he said.
‘Playing Chess With Cancer’
“There are many considerations about what to do at disease progression, including combination treatments, inhibition of KIT signaling, and more precise targeting based on dominant clone. We are in essence playing chess with cancer,” Dr. Sleijfer commented.
“In my view, treatment should be adjusted based on molecular evolution of the tumor. We have to identify which KIT mutations cause imatinib resistance. We need tools to assess mutational profile dominant clone and a randomized study comparing traditional treatment vs treatment based on mutational profile,” Dr. Sleijfer elaborated.
“Pazopanib is a novel [tyrosine kinase inhibitor], and it deserves further study. The outcomes of this study are in contrast to the Ganjoo et al single-arm study. At first glance these results are discordant, but the first study was conducted in a small number of heterogeneous patients. The study presented by Dr. Blay has a stronger design, and I agree that further study of pazopanib is warranted,” Dr. Sleijfer stated. ■
Disclosure: Dr. Sleijfer has received research funding from GlaxoSmithKline and Novartis.
