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MEDICAL FRONTIERS - ESMO Conference on Sarcoma and GIST

Milan, Italy / March 9-10, 2010

The efficacy of imatinib, the first tyrosine kinase inhibitor (TKI) approved for use in the treatment of GIST, has been one of the most compelling examples of therapies targeted at very specific molecular processes in tumour growth. Recently, understanding of the interaction between the genetic makeup of GIST and response to TKIs has advanced greatly. Eighty-five per cent of GIST exhibit a Kit mutation; of these, 13% have a Kit mutation at exon 9 and 66% at exon 11. Analysis of efficacy studies of imatinib show that response is much greater for exon 11 mutations than exon 9 mutations or so-called wild-type tumours, while progressive disease was less frequent among those with exon 11 mutations (Table 1). Another genetic marker of poor response is exon 18 PDGFRA D842V. Patients with moderate risk showing such a mutation would therefore be unlikely to benefit from adjuvant therapy.

Primary resistance to imatinib seems to be largely determined by genotype. Another issue with imatinib therapy is the development of secondary resistance, defined as patients showing initially good response or stable disease, then progressing usually after 12 to 36 months of treatment. Resistance generally results from mutations that reduce dependence of the tumour on Kit or that reduce the ability of imatinib to inhibit the enzyme. “The widespread standard of care would be to increase imatinib to 800 mg daily,” explained Dr. Jonathan Trent, M. D. Anderson Cancer Center, Houston, Texas.

Although an increase in dose is effective for overcoming resistance in many patients, there is now renewed interest in the use of alternative TKIs as second-line therapy. The most extensive data are available for nilotinib and sunitinib. Both have demonstrated good activity in GIST, leading to a series of studies attempting to determine a rational approach for substituting these agents. While GIST does not appear to be cross-resistant to these agents, the drugs also differ for tolerability. Relative to imatinib, Dr. George Demetri, Director, Center for Sarcoma and Bone Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, suggested that sunitinib might be more potent than imatinib. However, he added, “The downside is that it also has more side effects. It is smaller so it fits in different places. That is what we have seen clinically.”

Table 1.

Patterns of TKI Resistance by Exposure

One important question, particularly regarding decisions about maintaining or discontinuing adjuvant imatinib therapy, is whether the development of resistance is influenced by exposure to the drug. An answer to this question was provided by the BFR14 trial conducted by the French Sarcoma Group. Patients with advanced/metastatic GIST and stable disease or better with imatinib treatment were randomized to stop imatinib and restart once progression occurred or continue with imatinib (Figure 1).

Figure 1.

“In patients who stopped therapy, we see that by one year, the majority of patients had progressed. By two years, over 85% of the tumours had progressed, in contrast to patients who continued therapy,” reported Dr. Suzanne George, Clinical Director, Center for Sarcoma and Bone Oncology, Dana-Farber Cancer Institute. “But importantly,” she added, “when looking at the time to secondary resistance there was no significance difference between the two cohorts.” This provides further evidence that for good disease control, continuous adherence to the drug is necessary. She cautioned that suspension of imatinib therapy does not promote secondary resistance. “[Stopping imatinib even for a short time] is something that patients are very concerned about,” Dr. George commented.

The availability of TKIs such as imatinib has led the way to the possibility of neoadjuvant therapy for GIST. According to Dr. Peter Hohenberger, Head, Division of Surgical Oncology and Thoracic Surgery, Klinikum Mannheim University of Heidelberg, Germany, “Clearly, if we can shrink the tumour before surgery, it makes things easier.”

In the past, tumours would be classed as benign or malignant, but this was superseded by an approach whereby the risk of aggressive behaviour was quantified by taking into account the macroscopic size of tumour, site and mitotic rates. For example, a tumour =2 cm located in the stomach with a low mitotic rate is considered as having almost no risk of aggressive behaviour. The standard of care for local disease is resection of all tumours >2 cm, leaving 1- to 2-cm clear margins.

Neoadjuvant Imatinib

There are three major trials of imatinib in a neoadjuvant setting. Dr. Hohenberger presented preliminary surgical results from the Apollon study. “In 21 out of 25 patients, a less extensive procedure could be performed compared to recommendations by previous tumour boards,” he affirmed, although he cautioned against missing the best moment for resection, as “imatinib does not work indefinitely.” He cited the example of a patient with a shrinking tumour who refused surgery. The tumour started to grow again and had to be resected in a more aggressive procedure than the one the patient would have needed when the tumour had shrunk to its smallest size.

Recurrence of GIST following surgery is common, particularly in high-risk patients, in whom the median time to recurrence is two years. The risk of recurrence is determined by a number of factors such as tumour size, site and mitotic rate (DeMatteo et al. Cancer 2008;112(3):608-15). Thus, small bowel tumours and tumour rupture during resection are associated with a high risk of recurrence. Mutational status may also be important, with patients whose tumours harbour the so-called exon 11 Kit mutation are more likely to have better outcomes. In view of the risk of recurrence, there is a case for adjuvant therapy with TKI, an affirmation supported by the results of clinical trials.

The Z9000 phase II trial of patients with high-risk primary GIST (primary tumour size =10 cm, rupture during resection, multifocal tumour) demonstrated the feasibility and safety of adjuvant therapy with imatinib. Then last year, the findings of the placebo-controlled ACOSOG Z9001 trial were published (DeMatteo et al. Lancet 2009;373(9669):1097-104). Patients with primary GIST (=3 cm) underwent complete gross resection and were then randomized to placebo (n=354) or imatinib 400 mg daily (n=359) for one year. Patients on placebo who developed recurrence could cross over to active treatment. At median follow-up of 19.7 months, recurrence or death was significantly lower for patients on imatinib compared to patients on placebo (8% vs. 20%). A closer look at the data according to primary tumour size shows that the largest survival benefit was obtained for patients with tumours =10 cm (Figure 2, Graph C) whereas less but still significant benefit has been observed with those measuring 3 to 6 cm (Graph A). Three other trials with adjuvant imatinib are ongoing.

Patient Selection for Neoadjuvant Therapy

While the results of the Z9001 trial were positive, “a major issue with adjuvant therapy is correctly selecting the patients who stand to benefit,” stated Dr. Peter Reichardt, Helios Klinikum Bad Saarow, Germany. A retrospective analysis of recurrence with stratification according to the Fletcher classification (Fletcher et al. Hum Pathol 2002;33(5):459-65) showed no difference between placebo and active treatment for the low-risk group, a striking difference for the high-risk group, and a non-significant trend for the moderate-risk group. Analysis of the data according to the Miettinen classification yields a similar picture: a striking treatment effect for the high-risk group, no effect for the low-risk group and an almost significant result (P=0.0509) for the moderate-risk group. Yet Dr. Reichardt stressed that this would mean patients with moderate risk should not be treated because of a non significant effect: “The conclusion is that we should look more closely at this so-called moderate risk group.”

A large tumour (=10 cm) in the gastric location with a low mitotic index is classed as moderate risk. This relatively common tumour is known to have an indolent course with a limited tendency towards metastatic disease. Thus, the recommendation would be to treat patients in the high-risk group and not to treat patients in the low-risk group. In the remaining patients, treatment decisions should be guided by other considerations, such as mutational analysis.

Figure 2.

Dose and Duration of Adjuvant Therapy

The large trials with imatinib as adjuvant therapy used a dose of 400 mg. However, it has been suggested that certain patients, particularly those with an exon 9 mutation, might benefit from a higher dose. According to the recently published Meta-GIST analysis, which pooled the data from two studies that compared 400 mg once daily vs. 800 mg daily in patients with advanced GIST, a small benefit in progression-free survival (PFS) was observed, particularly among patients with a Kit exon 9 mutation. This would suggest that this patient group may benefit from a dose escalation, though it remains open to debate whether patients should receive the higher dose from the outset or wait until progression has occurred before increasing the dose.

Determining the duration of adjuvant therapy is more complex. The survival curve for the active arm of the Z9001 trial was essentially flat during the 12 months of treatment, and then started to drop after about 18 months (six months after stopping treatment) before starting to level off again after 30 months or so, though the number of patients was too small to provide reliable indications. Thus, according to Dr. Reichardt, “Starting treatment was a good decision, stopping was probably not a good decision, and long-term data are currently not available.” Reliable data for the duration of treatment in an adjuvant setting are not presently available. It is hoped that the ongoing Scandinavian Sarcoma Group (SSG) XVIII trial and the EORTC 62024 trial will provide firm data on the benefit of extended periods of treatment. The SSG XVIII trial, which has randomized 400 patients with high-risk GIST, is comparing relapse-free survival for 12 months vs. 36 months of imatinib. “This is an event-driven analysis so a date for completion cannot be given, but it is expected in the coming months,” Dr. Reichardt told delegates.

New Directions

Although imatinib and, to a lesser extent, sunitinib, have greatly improved PFS in high-risk patients, cure remains elusive. It is very hard to eliminate all residual cancer cells and resistance will usually develop eventually. There is therefore a need for new therapies. In his review of new candidate therapies, Dr. Demetri suggested that we would see new TKIs become available.

Summary

The arrival of TKIs such as imatinib has changed the standard of care for patients with GIST. Neoadjuvant therapy with imatinib is indicated for many patients awaiting primary tumour resection, while use of this agent is appropriate in many patients in the adjuvant setting, though careful patient selection is required to attain full benefit. Advances in the understanding of the different types of gene mutation present in GIST can also help to guide decisions about when to use imatinib and at what dose. Second-line therapy with nilotinib or sunitinib, alternative TKIs, may also be an option in patients with disease resistant to imatinib.