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MEDICAL FRONTIERS - 46th Annual Meeting of the American Society of Clinical Oncology

Chicago, Illinois / June 4-8, 2010

The definition of optimal treatment of gastrointestinal stromal tumours (GIST) is evolving quickly based on new findings. In the adjuvant setting, some new data are still emerging from the phase III study that provided imatinib, the small molecular inhibitor which has become the standard treatment of unresectable and metastatic GIST, with the adjuvant indication. In the ACOSOG Z9001 study, imatinib improved recurrence-free survival (RFS) when administered following resection of the localized, KIT-positive primary GIST tumour. In new data from this study, imatinib was found highly effective relative to placebo, specifically in GIST with KIT exon 11 and PDGFRA mutations. It also appeared to modify the increased risk of recurrence associated with mitotic rate, tumour size and location.

Prognosis After Surgical Resection

“There are several pathologic features and mutations that are prognostic and predictive for RFS after surgical resection of primary GIST, and these may be helpful in making treatment decisions going forward,” reported Dr. Christopher Corless, Chief, Surgical Pathology, Oregon Health & Science University, Portland. Its effect on mitotic rate and tumour size is not surprising based on previous data. Dr. Corless reported that imatinib consistently modified the influence of these factors and demonstrated greater efficacy than placebo for the most common types of mutations. In exon 11 mutations, which were the most common (68% of cases), the RFS at two years was 91% on imatinib and 65% (P<0.001) on placebo.

“These data come from the largest cohort of GIST patients receiving adjuvant therapy of any kind, and it confirms significant delays in progression with imatinib overall and specifically in several types of GIST stratified by mutation,” Dr. Corless told delegates. This also included greater twoyear RFS rates with imatinib relative to placebo in PDGFRA mutations (100% vs. 76%; P<0.01). The advantage of imatinib over placebo in wild-type GIST was not significant. The relative benefit in exon 9 mutation GIST, although protective in initial follow-up with the entire population, could not be evaluated in this more recent analysis because the number within this subgroup (35 patients) was small (Figure 1).

Of the 713 patients included in the published Z9001 results (DeMatteo et al. Lancet 2009;373:1097-104), 513 patients were included in the newer, more detailed analysis that was designed to observe prognostic factors over a longer follow-up. These were relatively evenly divided between imatinib (252 patients) and placebo (261 patients) even when stratified by tumour size and mitotic index. Overall, 40.7% had a tumour <5 cm (and >3 cm, which was an entry criterion), 33.5% had a tumour 5 to 10 cm and 25.7% had a tumour >10 cm. When stratified by a mitotic index of 5 mitoses per 50 high powered fields (5/50 HPF), 61% had a lower mitotic rate and 39% had a higher rate.

Preventing Recurrence

When prognostic factors in both groups were evaluated separately using multivariate analysis, the higher mitotic rate was the most powerful predictor of recurrence. In the placebo group, it produced a hazard ratio (HR) of 17.1 (P<0.0001), followed by location in the small bowel (HR 2.1 vs. the stomach; P<0.05) tumour size (HR 1.7 for tumours >5 cm vs. <5 cm; P<0.01) and location in the rectum (HR 1.3 vs. the stomach; P<0.05).

The prognostic factors were similar when the same multivariate analysis was conducted in patients who received imatinib. Again, the greatest predictor of recurrence, although smaller for imatinib than placebo, was a mitotic rate >5/50 HPF relative to a lower mitotic rate (HR 7.4; P<0.001) followed by location in the rectum (HR 5.4 vs. the stomach; P<0.05), location in the small bowel (HR 3.1 vs. the stomach; P<0.05) and tumour size (HR 2.9 tumours >5 cm vs. <5 cm; P<0.01).

Mitotic rate did correlate with tumour size but not with tumour location, remarked Dr. Corless, who noted that the 5/50 HPF cut-off appears to remain valid even though current microscopes provide more than double the visual field (11.87 vs. 5.3 _mm2) that was available to the microscopes used when this cut-off was developed. When the modern mitotic count was combined with size and location to define GIST as low, moderate or high-risk, there was a strong correlation with risk of recurrence. At a median follow-up of 19.7 months, recurrences occurred in 2% of the low-risk group, 24% of the moderate-risk group and 59% of the high-risk group.

While these new data reinforce and expand on the important benefits of adjuvant imatinib for preventing recurrence of localized resected tumours, new analyses from another large GIST dataset suggest that phase III data have already been largely incorporated into clinical practice. In a co-operative ongoing study called the reGISTry that has already enrolled 1053 patients at more than 100 centres, it was found that almost 90% of patients who undergo resection are receiving adjuvant imatinib. Reflecting the phase III study, the most common starting dose of imatinib has been 400 mg and the most common duration is 12 months, although the authors found that the duration of therapy did not appear to correlate closely with tumour size, site or mitotic rate. In fact, there has been some deviation from the entry criteria employed in the phase III study.

“The tumour size, mitotic count and tumour location all appear to be important for selecting patients for therapy and for predicting outcome, but not all of these factors are being recorded in all patients or appear to be routinely employed in decision-making,” stated Dr. Jonathan C. Trent, Department of Sarcoma Medical Oncology, M.D. Anderson Cancer Center, Houston, Texas. For example, he noted that some patients have received adjuvant imatinib in the absence of a known mitotic rate, although he ackowledged that “this may be due to overriding factors such as tumour location or size.”

Findings from International Registries

While the reGISTry is considered a mechanism to collect information about the treatment of GIST, Dr. Trent suggested that it may also provide a mechanism for disseminating information to clinicians about the role of risk assessment in developing a treatment strategy. In fact, another study generated by reGISTry data was designed to look at nonstandard dosing and further confirmed that there are significant deviations from evidence-based practice. This non-standard dosing, which typically resulted in doses less than 400 mg daily, were particularly common in the community setting when compared to the academic setting. The authors of this study, led by Dr. Peter W. T. Pisters, Department of Surgical Oncology, M.D. Anderson Cancer Center, expressed concern about the risk of suboptimal trough levels.

“Maintaining optimal imatinib dosing may improve long-term clinical outcomes, because imatinib trough concentrations <1100 ng/mL C_min are associated with a shorter time to progression and lower rate of clinical benefit,” Dr. Pisters explained. He further observed that based on the reGISTry data, a substantial number of patients who have progressed on imatinib 400 mg or who have a confirmed exon 9 mutation are not receiving the 800-mg dose now established as beneficial in clinical studies.

Very similar concerns about adherence to evidencebased management are being raised in metastatic GIST from a related dataset called the GOLD (Global Observational registry collecting Longitudinal Data on patients with advanced GIST) registry. While reGISTry is primarily enrolling patients receiving treatment for GIST at community and academic centres in the US, the GOLD registry is enrolling patients with locally advanced, metastatic or recurrent GIST at sites outside the US. The most recent analysis included 1065 patients enrolled at 156 sites in 34 countries distributed across western Europe, Canada, eastern Europe, Asia, Latin America and the Middle East.

Not all of the patients underwent a mutational analysis at the time of GIST diagnosis and an appropriate medical therapy did not appear to be offered to all eligible patients, according to Dr. Matias Chacon, Department of Medical Oncology, Alexander Fleming Institute, Buenos Aires, Argentina. Rather, 309 patients (29%) had surgery in the form of complete or partial resection of the primary tumour or a metastasis despite a low expectation of sustained benefit. Many of those surgically treated did not also receive the current standard medical therapy, which is supported by clinical trials.

The Case for Continous Treatment

In advanced and metastatic GIST, the evidence-based standard is imatinib 400 mg, although escalation to 800 mg is indicated in GIST with an exon 9 mutation. Although this therapy is not curative, responses are often sustained so that individuals can maintain an adequate quality of life with no disease-related symptoms for indefinite periods. However, new long-term data reinforce previous evidence that imatinib should never be discontinued in responding patients. In a prospective, randomized phase III study called BFR 14 that compared interruption vs. continuation of imatinib at five years in patients who continued to be relapse-free, the relapse rate in the 11 who stopped was almost 50% (five patients) vs. no relapses in the 10 patients who continued (P=0.035).

“In patients who are still responding, imatinib must be given continuously. Despite five years of disease control, there a substantially higher rate of progression when therapy was discontinued,” emphasized Dr. Isabelle Ray-Coquard, Department of Medical Oncology, Centre Léon-Bérard, Lyon, France. She noted that these most recent results reaffirm and amplify previous comparisons of interrupting or continuing treatment that was conducted in relapse-free patients at one and th
therapy (Figure 2).

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Regaining Disease Control

Once patients progress on the standard dose of 400 mg q.d., control can often be regained if the imatinib dose is increased to 800 mg daily. In patients who progress on the higher dose, other targeted therapies are being evaluated for second- and third-line therapy, including nilotinib and sunitinib, which are similar to imatinib but have different affinities for specific molecular pathways. There is now a growing number of studies demonstrating that these therapies can reintroduce control lost on previous treatment. For example, in a phase II study of nilotinib of 35 patients who had become resistant or intolerant to both imatinib and sunitinib, 28.6% were in disease control at the end of 24 weeks and the median progression-free survival was 113 days. This was a particularly encouraging result in a group of individuals with few remaining options because nilotinib was well tolerated.

“About 25% of patients developed nausea and vomiting of any grade, but grade 3 or 4 events were uncommon, and no patient developed a grade 3 or higher hematological toxicity,” reported Dr. Toshiru Nishida, Department of Surgery, Osaka University Graduate School of Medicine, Japan.

Similar findings were generated by preliminary results from a much larger phase III study called ENEST g3 that included 248 patients with advanced metastatic GIST who had failed imatinib or sunitinib. In this openlabel study, patients were randomized in a 2:1 ratio to nilotinib 400 mg twice daily or to an alternative plan selected by the treating physician. Most received best supportive care with imatinib or sunitinib, although a proportion received best supportive care alone. In the 197 patients who were identified as receiving a “true” third-line regimen because they had failed both imatinib and sunitinib, the median overall survival
days vs. 280 days (P=0.03) for the alternative plan (Figure 3).

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“Given the almost four-month improvement in true third-line patients, further study of nilotinib activity in a well-defined GIST population is warranted,” reported senior author Dr. Peter Reichardt, Chief, Department of Hematology and Oncology, HELIOS Klinikum Bad Saarow, Germany.

However, Dr. Reichardt is among several investigators who also believe that more studies are needed to evaluate individualization of therapy, including upfront use of such agents as nilotinib and sunitinib in patients with advanced GIST that has an unfavourable mutational status for response to imatinib. Several studies are underway or planned to improve rational treatment selection, suggesting further evolution in the management of GIST both early and late in the disease process.

Summary

The ability of adjuvant imatinib to substantially reduce the risk of recurrence after resection of primary GIST tumours is the most significant of a series of advances outlining how best to employ targeted therapy in this disease. In advanced GIST imatinib remains the gold standard, but more information about relative response to mutations may alter the sequence of second- and thirdline strategies or even suggest an alternative targeted therapy in first-line therapy when specific mutations are present. In advanced disease, there is now strong evidence that imatinib should be continued indefinitely, a strategy that might also be explored for adjuvant therapy administered in patients with a moderate to high risk of recurrence from GIST.