AdultImatinib plasma levels correlate with response
This presentation at the 2009 Connective Tissue Oncology Society meeting by Dr. Jonathan Trent offered several new observations for patients on imatinib. One hundred forty-two GIST patients underwent therapeutic drug monitoring from May 2008 to September 2009 at MD Anderson Cancer Center. Imatinib blood plasma levels were measured and minimum concentration or trough levels were calculated. Patient response was also tracked as part of this retrospective, observational study, which included both those with advanced GIST and those receiving adjuvant imatinib (approx. 20%).
Patients were ranked by imatinib plasma trough level and divided into four groups or quartiles labeled Q1 to Q4. Q1 patients had the lowest measurements, Q4 the highest. The upper cutoff for the lower quarter in this study was 910 ng/mL. It was noted that this level was lower than the earlier study of patients in the 2000-2001 Phase 2 STI-571 (Gleevec) trial. That study introduced the much discussed 1,100 ng/mL boundary. Reasons for the difference may include the larger size of the MD Anderson patient group and differences in the patient populations.
Note: It is perhaps also significant that this boundary number increased from 851 ng/mL in the earlier abstract to 910 ng/mL (+7%) in the actual presentation due to later data including just two more patients in this lower quartile and six more patients overall.
Patients who responded to imatinib therapy as measured by the Choi criteria had a significantly higher imatinib trough plasma level. Imatinib plasma level correlated with Choi response.
Higher doses and dose escalation resulted in higher imatinib levels. An imatinib dose escalation of 100 mg resulted in an average 296 ng/mL plasma level increase.
In this study imatinib trough plasma levels correlated with age, gender and dose, but did not correlate with race, body surface area, duration of imatinib treatment, or whether a patient had a gastrectomy, either partial or complete.
Patients with KIT exon 9 mutation imatinib, had higher plasma levels and had progression-free survival similar to that of patients with exon 11 mutation.
Dr. Trent also presented a protocol outline for a future clinical trial to study imatinib plasma levels under the sponsorship of the Sarcoma Alliance for Research through Collaboration (SARC019). Preliminary designs show recently diagnosed GIST patients are randomized to cohorts that do and do not adjust dose based on imatinib trough plasma level measurements. SARC019 design will explore the best Cmin (minimum concentration) for eventual use in the clinic.
Rechallenge with imatinib reported as possibility for patients without options
Clinical trial options may be limited when patients face resistance to standard GIST therapies. In this poster the authors ask if returning to imatinib after other options have failed has an active effect. They conclude that rechallenge with imatinib is feasible and can display some anti-tumor activity in patients with GIST resistant to standard and investigational therapies who lack alternatives. Seventeen resistant GIST patients in Italy were given imatinib (12 at 800 mg and 5 at lower doses). Two patients achieved partial response and five had stable disease. Four patients are alive and still on treatment. Median duration of imatinib rechallenge treatment for all patients was 105 days. Thirteen of the 17 were male. Mutation status was not reported and may have had some bearing on the result. (Abstract 39404 Rechallenge with imatinib in GIST patients resistant to second or third line therapy.)
GIST bone mets reported as rare but underestimated
A group of 288 advanced/metastatic GIST patients treated in Italy with tyrosine kinase inhibitors over seven years were reviewed. Fourteen patients (5%) developed bone lesions at a median 35 months after primary GIST diagnosis. In roughly half the patients bone mets were associated with other unusual metastatic sites (lung, soft tissue, spleen and parotid gland). The most frequent bone met sites were spine and pelvis. Four patients received radiation therapy and had subsequent pain relief. “In nine patients, tyrosine kinase inhibitors obtained a stabilization of bone disease with a metabolic response.” GIST bone mets are rare but more frequent in this study than previously reported. (Abstract 39410 Bone metastases in GIST: an underestimated occurrence.)
Possible new pathway targets modeled in vitro
This interesting presentation comes from the lab of Dr. Anette Duensing, an LRG Research Team member at the University of Pittsburgh Cancer Center. Dr. Duensing’s team has been exploring the signaling pathways that allow some GIST cells to survive imatinib therapy. Her team has explored cell defense mechanisms by which some GIST cells become dormant or “quiescent,” thereby avoiding exposure to apoptic effects of imatinib treatment in the natural cell division and growth cycle. These discoveries may lead to new targets in the lab and approaches that seek to eradicate all viable remnants of GIST. Proteins identified in human GIST cell lines include SKP2, p27(Kip1) and the human DREAM complex involving B-MYB, p130 and LIN37. (Abstract 39394 Imatinib modulates regulators of tumor cell quiescence in GIST cells.)
Bortezomib shown to kill resistant GIST cells in vitro
This presentation reported the work of three LRG-funded research team members, Dr. Sebastian Bauer of West German Cancer Center, Dr. Jonathan Fletcher of Brigham and Women’s Hospital in Boston, and Dr. Anette Duensing of the University of Pittsburgh Cancer Institute. At CTOS 2008, Dr. Duensing presented data demonstrating the role of the proteasome in GIST resistance. The proteasome is a special protein that recycles other proteins into their component parts. In GIST, the proteasome mechanism lowers levels of a protein, H2AX, that is involved in GIST cell death (apoptosis). Inhibiting the proteasome could therefore lead to GIST cell death. In this presentation, data is presented showing the effect of proteasome inhibitor bortezomib on resistant GIST cell lines. The report concludes, “Collectively our results show that inhibition of the proteasome using bortezomib can effectively kill imatinib-sensitive and imatinibresistant GIST cells in vitro and provide a rationale to test the efficacy of bortezomib in GIST patients.”
So far, anecdotal reports of bortezomib use in GIST have not shown any breakthroughs. (Abstract 39457 Pro-apoptic activity of bortezomib in GIST cells.)
At the 2009 Connective Tissue Oncology Society (CTOS) meeting there were several posters/presentations about pediatric GIST. One of the posters was from the NIH Pediatric & Wildtype GIST clinic and there was a presentation and a poster about the expression of two important proteins in pediatric GIST. The Consortium for Pediatric and GIST Research (CPGR) presented a poster of results from the first 39 patients to enter the National Institute of Health (NIH) clinic. This clinic is held twice a year and is a collaborative effort between clinicians, researchers, support groups and patients. All pediatric and wildtype GIST patients from any country are eligible to attend. Patients who wish to register for subsequent clinics should contact email@example.com.
Among the findings of the NIH clinic were that 7 of 39 (18%) of the patients had germline mutations in one of the genes that make up the succinate dehydrogenase complex (SDHA, SDHB, SDHC and SDHD). There were 4 patients with mutations in SDHB, 1 patient with a SDHC mutation and 2 patients with a SDHD mutation. Mutations in the succinate dehydrogenase (SDH) complex had already been reported by Dr. P. Aidan Carney, a retired pathologist at the Mayo Clinic and Dr. Constantine Stratakis, a pediatric endocrinologist at the NIH. The mutations previously reported by Carney and Stratakis were found in families of the syndrome. In the patients seen at the NIH clinic, only one family had a complex family history. Although longer follow-up is probably needed, this suggests that perhaps not all family members that have the mutation will develop clinical disease (penetrance may be incomplete). SDHB, SDHC and SDHD are known to be tumor suppressor genes. Mutations in these genes can cause several different types of cancer including GIST, paragangliomas and less frequently, renal cell carcinoma.
Other findings of the NIH clinic included an average age at diagnosis of 25.1 years, and average duration since diagnosis of 5.5 years and an average current age of 31.1 years. Females accounted for 79% of the clinic participants. Although tyrosine kinase inhibitors (TKIs) had limited effect in these patients (19% response rate), the majority of patients were doing well (95% overall survival rate and 23% in first remission) according to the authors. Dr. Katherine Janeway, a pediatric oncologist at Dana-Farber Cancer Institute, also gave a very interesting presentation on SDHB expression. Dr. Janeway and her colleagues looked at 15 KIT mutant GISTs (adult GISTs), 5 NF- 1 GISTs and up to 14 pediatric wildtype GISTs (they ran some through more tests than others). They found that the pediatric GIST tumors had a complete loss of SDHB expression (stained negative for SDHB). The adult GISTs stained positive for SDHB. They also found that the pediatric GIST samples tested had lost the function of complex II of the respiratory chain (in the mitochondria). This is interesting because it is what might be expected from the patients that had known SDHB mutations (Carney- Stratakis Syndrome), but would not be expected in pediatric patients that did not have that mutation.
Dr. Stratakis and Dr. Carney have previously reported that patients with Carney’s Triad might have a loss of one of the two copies of the SDHC genes. As noted previously, Stratakis and Carney and the NIH clinic participants have also found mutations in 3 of the genes that code for the SDH complex in patients with Carney-Stratakis Syndrome. However, loss of SDHB expression in Carney’s Triad and other forms of pediatric GIST is not due to mutations or deletions of SDBH, SDHC or SDHD. Instead, Dr. Janeway’s group is looking at the possibility of a different mechanism that might account for the loss of SDHB in other pediatric GIST patients. While the cause of SDHB loss remains unclear, their current hypothesis (work in progress) is that loss of SDHB is related to an epigenetic event. The authors concluded that “…these findings indicate that SDHB loss and defective cellular respiration may be central mediators of oncogenesis in pediatric GISTs lacking receptor tyrosine kinase mutations.”
Note: For more information on SDH mutations and Carney-Stratakis Syndrome, see the October 2007 edition of the Life Raft Group newsletter. Dr. Janeway and her colleagues at Dana-Farber also presented another poster about the overexpression IGF1R in pediatric GIST. This report of 9 pediatric GIST patients confirms previous reports of overexpression of IGF1R in pediatric GIST. The authors noted, “Clinical study of IGF1R-directed therapies in pediatric wildtype GIST is warranted.”
For a detailed description of IGF1R in pediatric and wildtype GIST, see the article by Dr. Michael Heinrich from the December 2009 issue of the LRG newsletter.