CHICAGO – More than 10 years on, nearly one-fourth of patients with gastrointestinal stromal tumors treated initially with imatinib are still alive, according to results from a collaborative trial reported at the annual meeting of the American Society of Clinical Oncology.
"A significant fraction of patients can survive for more than 10 years with imatinib [Gleevec] as their initial therapy for advanced GIST; and for almost half as their only systemic therapy for advanced GIST, understanding the pathobiology of these exceptional outcomes will be important to understanding the disease better," said Dr. George Demetri, director of the Center for Sarcoma and Bone Oncology, Dana-Farber Cancer Institute, Boston.
Dr. George D. Demetri
In the 14 years that have ensued since the first patient with GIST received imatinib and had an "extraordinary" response, new drugs in the tyrosine kinase inhibitor (TKI) class have become available for patients whose disease has progressed on the TKI imatinib. The evolution in the treatment of GIST emphasizes the fact that overall survival as a trial endpoint is really "a composite endpoint of on-study and poststudy interventions," Dr. Demetri said at meeting.
In the phase III Southwest Oncology Group (SWOG) Intergroup S0033 trial, initiated in 2000, 746 patients with metastatic or unresectable GIST were randomly assigned to receive daily imatinib at a dose of either 400 mg or 800 mg (400 mg twice daily). Patients in the 400-mg qd group had the option of crossing over to the 800-mg dose at the time of disease progression, and 130 patients chose to do so.
The trial was sparked by the discovery by Japanese investigators in 1998 of gain-of-function mutations in the gene encoding for KIT kinase.
As the SWOG S0033 investigators reported in 2008, median progression-free survival at a median follow-up of 4.5 years was 18 months for patients on the 400-mg dose and 20 months for those receiving 800 mg. The median overall survival was 55 months for patients in the 400-mg arm and 51 months for those in the 800-mg arm.
"A question we ask ourselves is, what accounts for this 33-month survival median difference after objective disease progression? It seems like a long time, which is why we wanted to know what happened to these patients after progression," Dr. Demetri said.
The investigators looked at survival by mutational status. Data on the GIST genotype were available on 395 patients, 282 of whom (71%) had KIT exon 11 mutations, 32 of whom (8%) had KIT exon 9 mutations, and 14 (4%) had other KIT or PDGFRA (platelet-derived growth factor receptor–alpha) mutations. Another 67 patients (17%) had no detectable KIT or PDGFRA mutations.
An analysis of data on these patients at 4.5 months’ median follow-up showed that patients with KIT exon 11 mutations had significantly better overall survival than patients with either wild-type (no mutation) KIT (P = .0011) or exon 9 mutations (P = .049).
Updated data with follow-up out to 10 years shows that patients with the KIT exon 9 mutation had significantly worse overall survival than patients with either exon 11 mutations (P = .0001) or no mutations (P = .047). There was no significant difference between patients with exon 11 mutations and no KIT or PDGFRA mutations.
Other factors significantly associated with overall survival in multivariate analysis included age by decade, male sex, performance status, maximum tumor diameter, and serum albumin (3.5 g/dL or less vs. more than 3.5 g/dL).
An analysis of on-study and postprogression therapies among 137 of 180 long-term survivors (8 years and longer) showed that 67 of the 137 (49%) had taken imatinib continuously as the only long-term therapy.
The remaining 70 patients (51%) had some additional therapy, including systemic therapies such as sunitinib (Sutent; 30% of the 137 patients), sorafenib (Nexavar; 12%), and other agents (31%).
In addition, 41 patients (30%) had metastasectomy or other type of surgery, 10 (7%) had radiofrequency ablation of tumors, and 6 (4%) had radiation therapy.
"We know that the landscape of therapeutic options for GIST has evolved greatly since this early large-scale study. We have new TKI therapies like sunitinib, sorafenib, and regorafenib [Stivarga], which has been approved for patients following progression of first-line imatinib, and we now accept the fact that multidisciplinary management of GIST, with resection of limited sites of oligoclonal resistant disease, is a standard option, with continuation of TKI therapy to control residual, unresectable disease," he said.
"Nonetheless , what the survival curves show us is that new options for management of KIT exon 9 mutant and other resistant genotypes are still needed," he concluded.