Evolution of Targeted Therapy: GIST Experience Points the Way to Defining Third-Line Treatment

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

A discussion of targeted antineoplastic therapy in the management of cancer based on the presence of a well-defined molecular target should no longer be considered an anecdotal story, as it was little more than a decade ago,¹ but rather a recognized standard-of-care approach in an increasing number of clinical settings.

In no malignancy has this change in disease management been more profound than in the case of gastrointestinal stromal tumor (GIST), which was once considered essentially untreatable if the disease recurred following surgical resection or was metastatic at presentation. The landmark observation that the driver mutations associated with the KIT and PDGFR-α genes in this cancer could be favorably impacted following treatment with imatinib rather dramatically changed the approach to therapy and, most importantly, anticipated outcomes.² In fact, a recent study has demonstrated the clinical utility and improvement in overall survival associated with the adjuvant administration of imatinib for three years in patients with a localized GIST but with features suggestive of a high risk for disease recurrence.³

Despite the truly impressive biological and clinical activity of imatinib documented in GIST, a not insignificant proportion of patients fail to respond to the agent or initially respond but subsequently develop resistance and experience progression of the disease. A second novel tyrosine kinase inhibitor, sunitinib, has been shown to produce meaningful clinical outcomes in this specific clinical setting.⁴ Unfortunately, while the majority of imatinib-resistant GIST patients appear to achieve a level of benefit from sunitinib, with median durations of disease control exceeding six months, progression ultimately develops.

Now, regorafenib, a novel drug with a different molecular inhibitory profile compared with imatinib and sunitinib, has recently been shown to be clinically active in the third-line setting in patients with GIST following failure of both of these approved antineoplastics.⁵ (In September, the FDA approved regorafenib for patients with metastatic colorectal cancer who have been previously treated with currently available therapies; Bayer HealthCare and Onyx Pharmaceuticals said last month that the FDA is considering their New Drug Application under the priority review program for patients with GIST whose disease has progressed after prior therapy with two kinase inhibitors).

Regorafenib, which appears to target a number of kinases in addition to KIT and PDGFR-α, was administered to a group of 34 patients with GIST who had failed therapy with both the standard first-line and second-line treatment approaches, plus possibly additional antineoplastic agents. Of this group, four individuals achieved a partial response while 22 did not progress for a period of at least 16 weeks (ie, stable disease).

Thus, as prospectively defined in this study, the overall clinical benefit rate (objective responses plus stable disease >16 weeks in duration) was 79%. In addition, the median progression-free survival for a patient population recognized as quite refractory was 10 months. Finally, even among the patient population demonstrating RECIST-documented progression, a small number were kept on active therapy by their treating physicians because of continued clinical evidence they were benefiting from the novel treatment regimen. At the time of this report, median overall survival in this trial population had not been reached.

Symptomatic side effects were quite common, and included hand-foot syndrome, fatigue, hypertension, and diarrhea. Fortunately, the majority of these events were not considered to be severe, although grade 3 toxicities were certainly not rare (eg, 36%, 24%, and 15% incidence of grade 3 hypertension, hand-foot syndrome, and hypophosphatemia, respectively).

These data, now confirmed in the results of a phase III randomized trial,⁶ provide strong support for both the biological and clinical activity of regorafenib as a third-line agent in the management of GIST. Further, the experience highlights the growing maturity of the concept of targeted antineoplastic therapy as a rational approach to disease management with therapy defined based on the unique and increasingly well-characterized molecular features of this particular tumor. It is reasonable to anticipate that other examples of beneficial sequential therapeutic strategies that employ knowledge of the biology of individual cancers will soon become commonplace in the oncologic therapeutic paradigm.

References

1. Joensuu H, Roberts PJ, Sarlomo-Rikala M, et al. Effect of the tyrosine kinase inhibitor STI571 in a patient with a metastatic gastrointestinal stromal tumor. N Engl J Med. 2001;344(14):1052-1056.
2. 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.
3. 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.
4. Demetri GD, van Oosterom AT, Garrett CR, et al. Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomised controlled trial. Lancet. 2006;368(9544):1329-1338.
5. George S, Wang Q, Heinrich MC, et al. Efficacy and safety of regorafenib in patients with metastatic and/or unresectable GI stromal tumor after failure of imatinib and sunitinib: a multicenter phase II trial [published online ahead of print May 21, 2012]. J Clin Oncol. 2012;30(19):2401-2407. doi: 10.1200/JCO.2011.30.9394.
6. Demetri GD. Randomized phase III trial of regorafenib in patients (pts) with metastatic and/or unresectable gastrointestinal stromal tumor (GIST) progressing despite prior treatment with at least imatinib (IM) and sunitinib (SU): GRID trial. J Clin Oncol. 2012;30(suppl;abstr LBA 10008).