Neoadjuvant Imatinib Associated With High Rate of R0 Resection in Large Gastric GIST

Yukinori Kurokawa, MD, PhD

Investigators conducting a small multinational study in Asian patients have concluded that 6 to 9 months of treatment with neoadjuvant imatinib (Gleevec) is a promising treatment for patients with large gastric gastrointestinal stromal tumors (GIST).

In results of a phase II multinational study (N = 53) published by the British Journal of Cancer, lead author Yukinori Kurokawa, MD, PhD, Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Japan, and co-authors found that neoadjuvant imatinib was associated with a high R0 resection rate and acceptable toxicity.

The R0 resection rate, the study’s primary endpoint, was 91% (95% CI, 79-97), much higher than the prespecified threshold of 70% (one-sided P <.001). In 79% of patients, at least half of the stomach was preserved with R0 resection (95% CI, 66-89).

“Neoadjuvant imatinib treatment may shrink tumor size remarkably and prevent tumor rupture during surgery, and thus lead to increased rates of complete resection. Indeed, the median shrinkage rate in this study was 35.4%, and no patients showed growth of primary tumors while receiving neoadjuvant treatment,” Kurokawa wrote.

“Furthermore, neoadjuvant imatinib could preserve the functioning of tumor-involved organs in many patients. Although our study included only large tumors (median, 12 cm) ~80% of the patients achieved preservation of at least half of the stomach, and only 3 patients (6%) underwent total gastrectomy.”

The objective best response rate and the disease control rate by RECIST were 62% (95% CI, 48-75) and 100% (95% CI, 93-100), respectively. The objective best response rate and the disease control rate by the Choi criteria were 98% (95% CI, 90-100) and 100% (95% CI, 93-100), respectively. Researchers observed favorable tumor shrinkage even in 2 patients with wild-type GIST (40.8% and 50.5%).

Previous studies, including retrospective case series and a small prospective study of only 14 patients, have assessed the feasibility of neoadjuvant imatinib in this setting. In 2 phase II studies, RTOG0132 and APOLLON, neoadjuvant imatinib was associated with R0 resection rates of 68% and 71%, respectively.

However, these studies included heterogeneous tumor characteristics (size, risk classification, tumor location), so it was difficult to evaluate the efficacy of neoadjuvant imatinib. For this reason, Kurokawa et al designed this single-arm study to investigate the efficacy and safety of neoadjuvant imatinib only in patients with large (≥10 cm) gastric GISTs.

From February 2010 to September 2014, patients received 400 mg once-daily of oral imatinib for 6 months as neoadjuvant treatment. Patients were taken off-study if researchers observed progressive disease at 1 or 3 months after starting treatment. Patients determined to have complete or partial response at 6 months could continue imatinib treatment for another 3 months.

Patients underwent surgery within 1 month of final evaluation of neoadjuvant treatment, and treatment was finally discontinued within 1 week of surgery.

Overall, 46 patients (87%) completed at least 6 months of treatment.

Fourteen patients required dose reductions due to toxicity, 10 due to nonhematologic toxicity. The most common nonhematological toxicities were any grade edema of the head and neck (72%) followed by any grade rash (45%). One patient experienced grade 4 cerebrovascular ischemia. Grade 3/4 neutropenia and rash occurred in 8% and 9% of patients, respectively. There were no treatment-related deaths.

Vicky Keedy, MD, associate professor of medicine in the division of hematology/oncology and clinical director of sarcoma at the Vanderbilt-Ingram Cancer Center, reviewed the data for OncLive. She said the results seem reliable because they appear to mirror what physicians see clinically and anecdotally. Further, extending the treatment up to 9 months may explain why the R0 resection rate is higher than historical data results because the researchers treated patients closer to maximum response.

However, she added that the patient population is small and the study was not randomized, so it is difficult to make comparisons without a control arm.

“It does help support what we’re already doing clinically. Many of us are doing neoadjuvant treatment in patients who have tumors that are large or are in difficult locations,” Keedy said. “It also shows us that it’s safe. None of the patients had perforations; very few patients had progression while on-treatment.”

Kurokawa Y, Yang H, Cho H, et al. Phase II study of neoadjuvant imatinib in large gastrointestinal stromal tumors of the stomach [published online May 23, 2017]. Br J Cancer. doi:10.1038/bjc.2017.144.