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Highlights from ASCO 2007

This year at ASCO, over 50 posters and presentations were given related to GIST. This article covers some of the GIST highlights.

Wound Healing

Dr. C.P. Raut and his Dana- Farber colleagues presented a poster about wound healing and surgery during sunitinib treatment. They compared complications from wound healing after surgery in patients on sunitinib therapy versus those on imatinib therapy.

Their conclusions were:

1. In this study, there were no significant differences in woundhealing complication following cytoreductive procedures between patients with metastatic GIST on sunitinib or imatinib therapy, despite the broader spectrum of RTK inhibition by sunitinib.

2. Given the relatively small sample size (sunitinib = 26, imatinib = 46), and the retrospective nature of this analysis, further studies will be required to confirm these results.

3. The current practice is to continue sunitinib until 1-2 days prior to surgery and to resume as soon as possible after hospital discharge, which usually coincided with the patient's first postoperative visit.

For details, see abstract #10044.

Congestive Heart Failure

Dr. A. Y. Khakoo and colleagues at MD Anderson presented a poster describing the “Rare incidence of congestive heart failure in GIST and other sarcoma patients receiving imatinib therapy”. They reviewed 219 patients enrolled on imatinib trials and concluded congestive heart failure was rare and only observed in one elderly patient with known prior cardiac disease. They also recommended that patients who develop potential cardiac adverse events (PCAEs) while on imatinib should be treated with diuretics, ACE-inhibitors and beta-blockers with continuation of imatinib as clinically indicated.

Nilotinib Phase I

Updated results for “a phase I study of nilotinib (AMN107) alone and in combination with imatinib in patients with imatinib-resistant GIST” were presented in abstract form by Dr. Margeret Von Mehren of Fox Chase Cancer Center. In this study of heavily pretreated patients, 18 patients received nilotinib alone and 35 patients received a combination of imatinib and nilotinib (in different dose combinations).

Median progression-free survival for this phase I trial was 134 days (about 4 ½ months) overall and 178 days (about 6 months) for patients receiving nilotinib alone. Six patients experienced dose limiting hyperbilirubinemia or skin rash. See abstract 10023 for more details.

NOTE: This phase I trial is now closed. The phase III trial is now open at three sites in the U.S. Fox Chase in Philadelphia, Pa., Dana Farber in Boston, Mass. and Washington University in St. Louis, Mo. Ten sites in total are planned in the U.S. Four are planned in Canada. Four sites are open in Europe. One site each is open in Taiwan and Australia.

Hypoglycemia

Dr. B. Rikhof and colleagues presented an abstract reporting on their experience with non-islet cell tumor induced hypoglycemia (NICTH) in GIST patients. They found that before treatment and/or during follow-up, four of 25 (16%) GIST patients showed increased plasma levels of a protein called ‘big’-IGF-II. Three of these four patients developed NICTH. ‘Big’-IGF-II is a high molecular weight form of IGF-II. According to Rikhof, “The role of IGF-II in GIST is unknown.”

Similar reports of NICTH and hypoglycemia (low blood sugar) have been reported in GIST patients by Davda et al., Escobar et al., Guiteau et al., Hamburg et al. and Pink et al.

Compliance and Medical Costs

Dr. R. Halpern and colleagues presented abstract 6618 describing the relationship between compliance with imatinib and medical costs for patients with CML and GIST. They reviewed past claims data from a large national US health plan. Compliance was measured with a medication possession ratio ((days of imatinib during follow-up / days of follow- up)*100). The compliance categories were; good compliance was equal to or better than 90 percent; medium compliance was between 70 and 89.9 percent and poor compliance was less than 70 percent. Only 35 percent of GIST patients had “good compliance”. The compliance was rated as poor in 46 percent of GIST patients and in 40 percent of CML patients. Mean medical costs across all patients were lower and less variable with good compliance ($22,882 ± 22,791) than with medium ($40,366 ± 68,186), p=0.007) and poor ($104,961 ± 190,559), p<0.001). Mean medical costs for GIST patients were: good=$28,318 (±24,781); medium=$ 33,270 (±35,356, p=0.584); and poor=$62,235 (±68,751, p<0.001). The authors concluded “Good imatinib compliance was associated with significantly lower medical costs. Mean total medical costs were 78 percent lower with good compliance relative to poor. Compliance is an important treatment issue for both clinical and medical cost outcomes.”

Sutent Resistance

Dr. Michael Heinrich gave an oral presentation “Mechanisms of sunitinib malate (Sutent) resistance in (GISTs).”In this study of two GIST patients (one with an exon 11 primary mutation and one with an exon 9 primary), a total of 11 lesions (tumors) were analyzed; nine of the eleven were progressing lesions. As Dr. Heinrich and colleagues have previously reported, resistance to sunitinib was highly correlated with secondary mutations. Lesions with secondary mutations in the drug binding pocket (exons 13 and 14) become insensitive to imatinib but retain their sensitivity to sunitinib. Lesions that developed secondary mutations in the KIT activation loop (exons 17 at codons 816, 820, 822 and 823) and in the extended activation loop (exon 18) were resistant to both imatinib and sunitinib.

A novel mutation was discovered inexon 16 (L783V) of one progressing lesion. sunitinib was able to achieve 50 percent inhibition of the in-vitro signaling of this type mutation at a fairly low concentration, however; it was unable to achieve 90 percent inhibition (IC90), even at high doses. The exon 16 mutation was clinically resistant to sunitinib, but the biochemical data for this was less clear according to Dr. Heinrich.

In his conclusions, Dr. Heinrich noted that sunitinib activity in imatinibresistant GIST is affected by the type of secondary KIT mutation as shown by invitro and clinical data. Dr. Heinrich also hypothesized that the anti-angiogenic effects of sunitinib may be insufficient to inhibit GIST progression when the targeted oncogenic kinase (KIT) remains active.