Imatinib Therapy Matures: GIST Research Sheds Light on Mutations, Drug Levels

Maurie Markman, MD

Editor-in-Chief of OncologyLive

Senior vice president for Clinical Affairs and National Director for Medical Oncology Cancer Treatment Centers of America, Eastern Regional Medical Center

The observation that imatinib, the paradigm-changing agent in the treatment of chronic myeloid leukemia, was also a highly biologically and clinically active drug against gastrointestinal stromal tumors (GISTs) rather dramatically altered both the management and prognosis for this rare disease.¹ More than a decade later, imatinib has developed from a novel therapy into an anticancer staple, and researchers continue to uncover the molecular complexities of optimally deploying this targeted agent against GISTs.

For example, as recently reported, three years of adjuvant treatment with imatinib in high-risk GIST was shown to improve both recurrence-free and overall survival compared with one year of this therapy.² This outcome raises the highly provocative question of whether treatment should be continued longer than three years, and perhaps indefinitely (assuming acceptable toxicity).

Approximately three-quarters of patients with GIST tumors will be found to have an activating mutation in KIT, with as many as one-quarter of such tumors possessing an activating mutation in a second gene that codes for the receptor for platelet-derived growth factor alpha (PDGFRA). Of note, in the initial efforts to utilize imatinib in the management of GIST, the presence of specific mutations within individual tumors was not routinely considered as predictive of the clinical utility of the agent, with all such patients being considered equally appropriate candidates to receive this drug.

However, recently reported data challenge this view by demonstrating that the presence of a specific mutation in PDGFRA (PDGFRA-D842V) predicts for the lack of activity (no responses in 31 patients) for the agent.³ Further, the median progression-free survival for patients treated with imatinib who possessed this mutation was only 2.8 months compared with 28.5 months for individuals with other PDGFRA abnormalities. Overall survival was also substantially reduced in the population with PDGFRA-D842V mutations.

These data suggest the decision to administer imatinib in GIST requires more than simply confirming the histological diagnosis or even the presence of an activating mutation. Rather, it is essential that the specific molecular abnormality be characterized and, in the presence of a PDGFRA-D842V mutation, alternative strategies should be considered, including participating in clinical trials that are examining novel antineoplastic drugs in this clinical setting.

A second report explored the impact of the prolonged administration of imatinib in patients with GIST and noted a decrease of about 30% in systemic exposure to the agent approximately three months after the initiation of therapy compared with a baseline determination.⁴ Whether this provocative observation is due to a change in absorption, metabolism, or perhaps even an element of patient nonadherence to taking the medication after prolonged use remains to be defined.

However, this feature may be a relevant clinical factor in the population of individuals who fail to adequately respond to therapy, or who respond to imatinib and subsequently experience evidence of progression of the disease process. Measurement of imatinib drug levels in such patients may provide an explanation and suggest a rational strategy to optimize the beneficial effects of treatment.

This experience also serves as an important reminder that the adequacy of exposure of the tumor to the antineoplastic drug is as essential for the success of a targeted therapeutic as it is for standard cytotoxic agents. Further, the data raise the question of whether this observation may be a more common event among targeted anticancer agents than currently recognized. At the time of documented tumor progression, it might be reasonable to examine drug levels as one possible explanation for the unfavorable clinical outcome.

Finally, considered together, these two recent reports serve to highlight the increasing maturation of efforts to optimize the effectiveness of molecularly directed therapy in routine cancer management.^3,4

References

1. Demetri GD, von Mehren M, Blanke CD, et al. Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N Engl J Med. 2002;347(7):472-480.
2. Joensuu H, Eriksson M, Hall KS, et al. One vs three years of adjuvant imatinib for operable gastrointestinal stromal tumor: a randomized trial. JAMA. 2012;307(12):1265-1272.
3. Cassier PA, 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 [published online ahead of print June 20, 2012]. Clin Cancer Res. 2012;18(16):4458-4464. doi: 10.1158/1078-0432.CCR-11-3025.
4. Eechoute K, Fransson MN, Reyners AK, et al. A long-term prospective population pharmacokinetic study on imatinib plasma concentrations in GIST patients [published online ahead of print July 31, 2012]. Clin Cancer Res. 2012;18(20):5780-5787. doi: 10.1158/1078-0432.CCR-12-0490.