Correlation of Long-term Results of Imatinib in Advanced Gastrointestinal Stromal Tumors with Next-Generation Sequencing Results: Analysis of Phase 3 SWOG Intergroup Trial S0033

Abstract

Importance

Initial results of this intergroup trial of imatinib for patients with metastatic/ unresectable GIST were reported in 2008 ( http://www.ncbi.nlm.nih.gov/pubmed/18235122). Updated results reported here show long-term survival with a significant subset of patients surviving 10 or more years, as well as new molecular disease insights.

Obective

To determine long-term survival of patients treated on SWOG study S0033, and to present new molecular data regarding treatment outcomes.

Design, Setting and Participants

Patients were required to have advanced GIST that was not surgically curable. Updated clinical information was obtained, including post-progression therapies. Using modern sequencing technologies, we analyzed 20 cases originally classified as “wild-type”. This intergroup study was coordinated by SWOG, a cooperative group member within the National Clinical Trials Network, with participation by member/affiliate institutions.

Interventions

Patients were randomly assigned to one of two dose levels of imatinib: 400 mg once daily vs. 400 mg twice daily, and were treated until disease progression or unacceptable toxicity.

Main Outcome Measure

The primary end point was overall survival. The primary aim of this report was to correlate updated survival with clinical and molecular factors, as well as to enumerate and describe patterns of post-imatinib therapies in long-term survivors.

Results

Of 695 eligible patients, 189 survived 8 years or longer, 95 on the 400 mg dose arm and 94 on the 800 mg arm. The 10-year estimate of overall survival (OS) is 23%. Among 142 long-term survivors, imatinib was the sole therapy administered in 49%, with additional systemic agents administered to 54 patients (38%). Resequencing studies of 20 cases originally classified as KIT/PDGFRA wild-type GIST revealed that 17 (85%) harboring a pathogenic mutation, most commonly a mutation of a subunit of the succinate dehydrogenase (SDH) complex. We report the first data on SDH-deficient GIST patients treated with imatinib in a prospective therapeutic study.

Conclusions and Relevance

A subset of patients with metastatic GIST enjoys durable long-term overall survival on imatinib. Although this study provides guidance for management of GIST harboring the most common KIT and PDGFRA mutations, optimal management of other genotypic subtypes remains unclear.