Barbara Dore’ (a member of GSI’s board and our science committee) attended the CTOS meeting in London November 13-15 on behalf of GIST Support International. This news story highlights some of the new science findings Barbara gleaned at CTOS, which is the world’s premier gathering of sarcoma experts. You can view the program listing at the CTOS website. Eventually CTOS will post all abstracts, plus slides from the oral presentations, on their site, but this may take a while. Barbara also attended the EORTC and SARC trial report meetings held prior to CTOS.

Highlights from the SARC Meeting

Fletcher on GIST Signaling

Jonathan Fletcher, MD of Dana-Farber gave a summary about GIST at the beginning of the SARC meeting entitled “Laboratory Investigation of Resistant GIST.” Focusing on imatinib resistance, he reviewed which mutations are susceptible to treatment with sunitinib (exons 9 and 13) versus those that are also resistant to sunitinib (exon 17). He stressed that tumors can be heterogenous, showing different secondary mutations in different clones within the same tumor.

von Mehren on IGF signaling in GIST

Margaret von Mehren, MD of Fox-Chase Cancer Center gave a lecture entitled “New Approaches to GIST” during the SARC meeting. She summarized the recent findings from the lab of Andrew Godwin, PhD regarding expression and activity of insulin-like growth factor receptor 1 in wildtype GIST, both pediatric and adult. IGF signaling is involved in the high glucose metabolism that makes most GISTs light up on PET scans. Overexpression of IGF genes in cancer correlates with increased progression. In GIST, higher IGF1 expression corrrelates with higher mitotic index and larger tumor size. Because single agent therapy (such as imatinib) is not curative for GIST, combination therapies are needed. Fox-Chase researchers plant to determine the role of IGF-1R inhibition in therapy for GIST. Dr. von Mehren and Dr. Katherine Janeway of Dana-Farber will co-chair a new Phase II trial to open soon for wildtype GIST patients (SARC 015).

Trent on dasatinib trial for sarcomas including GIST

Jonathan Trent, MD PhD of MD Anderson Cancer Center discussed the SARC 009 trial of dasatinib for metastatic sarcoma that opened in May 2008. So far 22 GIST patients have enrolled who are all either resistant to imatinib or imatinib-intolerant. Some have previously taken sunitinib. The trial also includes many more patients with other sarcomas. A third of patients have needed a dose reduction due to adverse effects. It is too early yet to predict results, but dasatinib is hoped to have activity against primary and secondary mutations that are resistant to imatiniib. There may be a role for combining kinase inhibitors, such as imatinib + sunitinib, or imatinib + sorafenib. Other potential strategies for GIST include:

• HSP90 inhibitors
• HDAC inhibitors
• Broader spectrum KIT inhibitors with downstream targets including PI3 Kinase and AKT
• small interfering RNA to target PKCTheta and PI3K
• KIT degradation: HSP90 inhibitors, HDAC inhibitors, protease inhibitors
• KIT synthesis inhibition
• Flavopridol
• KIT-independent pathways BRAF and IGF-1R

Highlights from the CTOS Meeting

Drug Development and Trial Design

The one-hour Nina Axelrad Lecture was given by Paul Meyers, MD, who is vice-chair of the Department of Pediatric Oncology at Memorial Sloan Kettering Cancer Center. His topic was “Development of a New Drug: Lessons from clinical trials.” Because the treatment of sarcomas with conventional agents (chemotherapy, radiotherapy) has shown little or no improvement in patient outcomes, the advent of targeted therapy is very hopeful. The way forward is possibly a combination of biological agents and chemotherapy. He discussed how clinical trial design is important in detecting the possible benefit from drugs. Some drugs are best used in an adjuvant setting, with minimal disease present (such as after tumor excision). The choice of the endpoints to measure – such as overall survival (OS) versus progression-free survival (PFS) affects how helpful the trial drug may appear. If the trial drug involves the activation of the immune system, and you want test if the agent is more effective on its own or in combination with a certain chemotherapy, then this is best detected in a Phase III combined trial. Dr. Meyers argued that it is not enough to capture PFS in Phase II trials, that it is important to continue to follow up those patients as long as it takes to get OS data by keeping the trial running. Regulators also prefer OS to PFS. Some of the physicians present regretted publishing Phase II data showing some patients progressed when if they had waited for Phase III data , then OS may have shown benefit – and low PFS in Phase II may prevent further trials.

Pediatric and Wildtype GIST

Dr. Su Young Kim, a pediatric oncologist at NIH, gave a poster presentation about the NIH clinics for pediatric and wildtype GIST. Barbara had her photo taken with him next to the NIH poster (below). You can see the poster at this link.

Sunitinib

Christopher Garrett, MD of MD Anderson Cancer Center presented a poster entitled “Long term survival in a Phase III trial of Sunitinib in imatinib resistant/intolerant GIST with novel statistical analysis to account for crossover.” This dealt with a re-analysis of the Phase III sunitinib trial to account statistically for the decrease in apparent efficacy of sunitinib due to the crossover to sunitinib by the patients who had shown progression in the placebo group. Interim analysis of this double blind, placebo controlled Phase III trial with crossover revealed a significant difference in overall survival (OS) between patients randomised to sunitinib vs placebo favouring sunitinib. However conventional statistical methods gave rise to biased estimates of treatment effect for mature OS data due to the crossover design. This reanalysis evaluated mature survival results using a novel statistical method to account for the effect of crossover on survival. It also included additional patients who had not yet been accrued in the interim analysis. Conclusion: The long term OS benefit provided by sunitinib (median 73.9 weeks) vs placebo (median 35.7 weeks by reanalysis) in this Phase III study was confirmed using RPSFT analysis.

Beatrice Seddon, MD of University College Hospital presented a poster updating survival and drug safety and side effects in the worldwide patients in the sunitinib treatment-use trial (providing Sutent to patients living where it is not yet approved for prescription). The most common non-hematologic grade 3 or 4 side effects were fatigue, hand-foot syndrome, hypertension, and diarrhea. 10% of patients developed hypothyroidism. Hematologic side effects included anemia, thrombocytopenia, and neutropenia. Hear problems were limited to less than 1% of patients. Median overall survival is longer in those patients who were intolerant of imatinib (median 97 weeks) than in those who developed imatinib resistance (median 60 weeks for primary resistance, 75 weeks for secondary resistance).

Paolo Casali, MD of the Instituto Nazionale Tumori in Milan presented a poster investigating how soon sunitinib might be started following stopping imatinib. In 6 patients who began taking Sutent 24 hours after the last dose if imatinib, side effects were comparable to patients who had a longer washout period. The investigators concluded that “sunitinib administration 24 hours after the lst dose of imatinib appeared to be safe and well tolerated.”

Pfetin as a GIST Biomarker

Yoshiyuko Suehara, MD PhD made an oral presentation entitled “Pfetin as a Prognostic Biomarker of Gastrointestinal Stromal Tumors Revealed by Proteomics,”
co-authored by others from Tokyo, Japan. This talk was one of two Young Investigator Award lectures. This research group wanted to identify commonality among the proteins in GIST tumours with the worst outcomes. They used ‘proteomics’ to identify the proteins present in GISTs with the worst prognosis. From GIST cell proteins they identified 43 spots on gel electrophoresis which represented 25 gene products, and 8 of the 43 spots derived from Pftein, four of which were highly discriminatory for good and poor prognoses. Pfetin expression and tumour metastasis were inversely related. Immunohistochemistry of 210 GIST patients also showed that the 5 year metastasis free survial was 93.0% for pfetin-positive tumours, compared with 36.2% for pfetin-negative tumours. The authors hope that this finding may lead to a way to reduce GIST metastasis.

Radiation Treatment of GIST Metastases

From the Royal Marsden Hospital, J. Hurwitz et al (including Ian Judson, MD) presented a poster entitled “The Role of Radiotherapy in Metastatic GIST.” Their aim was to assess the role of palliative radiotherapy for locally progressive and/or symptomatic metastatic GIST. Twelve patients were treated with radiation generally comprising 30 Gy in 10 treatments over 2 weeks. Sites treated included bone metastases, intra-abdominal or pelvic metastases, and the abdominal wall. Result: Radiation yielded effective, durable symptom control with minimal side effects, especially in the pelvis.

Proteasome Inhibition in GIST

Anette Duensing, MD of the University of Pittsburgh presented new findings about the potential of proteasome inhibition in GIST treatment. See a separate story about her work.