2013 ASCO GIST Presentations
Two dedicated GIST Support International volunteers, Nancy Berezin and Phyllis Gay, attended the giant 2013 ASCO meeting in Chicago to gather new information relevant to GIST. Both Nancy and Phyllis are members of the GSI Board and the GSI science committee. We all owe them thanks for making the trip on our behalf and working hard to summarize new findings for GIST patients.
Phyllis (left) and Nancy (right) are shown in this photo with the Chicago skyline.
ASCO 2013: Clinical and Basic Science Update
by Nancy Berezin
Following are some highlights of the GIST research presented at this year’s ASCO meeting. Unlike 2012 -- when Stivarga was rolled out with great fanfare -- no dramatic clinical breakthroughs were announced. But there has been continued progress behind the scenes, on the basic science front.
Mutation Testing for GIST Using Blood Samples
Most notably, 2013 saw development of a technique for detecting resistance mutations in GIST DNA circulating in the bloodstream – a method that is both more accurate and less invasive than traditional tumor biopsy. Two separate research teams – a German group led by Dr. Nikolas von Bubnoff (abstract 10508), and an international group led by Dr. George Demetri (abstract 10503) – reported similar findings using somewhat different technologies.
As described by Dr Demetri: GIST tumor tissue is often heterogeneous within a single patient; there may even be different mutations present at isolated locations within the same tumor. Thus, traditional methods of tumor biopsy may or may not pick up all the resistance mutations that are present when a patient has metastatic GIST. The insight leading to this year’s breakthrough was that tumor tissue is continuously dying and releasing free DNA into the patient’s circulation. Amplification of this DNA using a sophisticated technology known as BEAMing Digital PCR (developer: Inostics) can provide a comprehensive, real-time picture of the tumor genome with no need for invasive biopsies.
Using samples from participants in the Phase 3 regorafenib trial, who were already resistant to imatinib and sunitinib, Dr. Demetri and colleagues were able to show that BEAMing technology was far superior to standard tissue analysis -- identifying resistance mutations in 48% of blood samples vs 12% of tissue samples tested. Nearly half of patients with secondary KIT mutations were found to have more than one mutation.
Recapping these findings, Dr. Jon Trent told the audience that knowing the molecular profile of a patient's entire GIST burden -- as opposed to just the random bits revealed through tumor biopsy -- will permit oncologists to select the optimal drug or combination for that profile. And because the blood test can be performed repeatedly at minimal discomfort to the patient, it permits a more rapid response to changes in the mutational landscape. BEAMing technology should also streamline drug development by helping researchers design narrowly focused agents that can strike their molecular targets without causing the degree of toxicity that often accompanies agents with broader activity.
Drug Pipeline News
Of course, the wheels of drug development grind much more slowly than we, as patients, would like. However, a number of promising agents are currently in or entering clinical trials. These include:
MEK inhibitor (MEK162) to target ETV1, co-developed by Novartis and Array Biopharma.
A small Phase 2 trial (with a Phase 1 component) begins recruitment this summer at Memorial Sloan-Kettering Cancer Center. Forty-five patients with newly diagnosed advanced GIST will receive the experimental agent in combination with imatinib. While this is a long shot, it is an exciting one, as the two-drug combination could theoretically stop tumor growth in its tracks. ETV1 is a transcription factor that is essential to the development and survival of GIST. Without signaling from MEK, however, ETV1 can’t do its job properly. Interestingly, the MEK inhibitor does not seem very effective when used alone. When used in conjunction with imatinib, however, response is dramatically heightened.
Ponatinib (Iclusig), a multi-kinase inhibitor developed by Ariad.
Recently approved for treatment of CML, ponatinib is poised to enter GIST clinical trials in patients already resistant to imatinib. In vitro data (abstract 10509) showed that the drug potently inhibits KIT exon 11 primary mutations as well as secondary mutations at the KIT-ATP binding pocket and in the activation (A) loop, an area where sunitinib has been shown to be weak. However, ponatinib appears less effective in patients with KIT exon 9 primary mutations or secondary mutations involving V654A. (An example of the importance of molecular profiling alluded to earlier.) The investigators predict that once daily dosing with 45 mg ponatinib will be sufficient to achieve broad efficacy, which could mean relatively low toxicity compared to agents that require higher doses to produce meaningful results.
Masitinib, developed by AB Science.
The French developers had no exhibit at ASCO, and there were no abstracts or posters featuring the drug. Yet data continue to suggest that masitinib could be a valuable second-line agent or even compete for imatinib's spot as first-line drug of choice for the majority of GIST patients. A Phase 3 trial comparing masatinib to sunitinib is ongoing at several centers in the US and Europe, and a Phase 3 trial against imatinib is in the works. Side effects appear to be well tolerated.
Crenolanib, developed by AROG.
The Phase 2 trial of crenolanib remains open at two sites: Fox Chase and Oregon Health & Science University. The trial population consists exclusively of patients with advanced, previously treated GIST with PDGRFA D842-related mutations and deletions. Target enrollment is 20; to date,18 patients have signed up. Four dosage levels of crenolanib will be evaluated. (The original study protocol has been amended to allow higher dosing levels, in response to information gained from ongoing studies in pediatric brain tumor patients and adults with relapsed AML.) Thus far, side effects have been modest and well tolerated.
Pipeline drugs for pediatric and wild-type GIST did not receive coverage at this year's ASCO. However, the Phase 2 linsitinib trial is currently underway at multiple US centers. Hopefully, recent progress on the laboratory bench also will lead to more and better treatment choices for this underserved population.
More GIST Topics at ASCO 2013
by Phyllis Gay, PT
Below are sumaries of several poster presentations at ASCO 2013 that merit discussion and review:
Abstract #10590 Evaluating Surgery and First-line Imatinib Treatment Patterns for Patients with Gastrointestinal Stromal Tumors (GIST)
Since the approval of Imatinib in 2002 for advanced metastatic GIST, many GIST patients have been placed on imatinib (Gleevec). In 2008, imatinib was recommended for adjuvant GIST management as well. This study examines the changes in treatment trends for the years of 2003 to 2006 as compared to the years of 2007 to 2009. Records for 303 patients were included, many of whom used imatinib first with second-line treatment with an additional drug. In the most recent years, GIST patients have been placed on additional third and even fourth-line drug treatments.
There has been an obvious change in the presentation of the patients as seen in their first clinical encounter in recent years. The percentage of GIST patients with metastatic disease at first clinical presentation has decreased from 54.9% (2003 to 2006) to 36.1% (2007 to 2009). GIST patients undergoing a surgical procedure before use of imatinib has more than doubled 10.4%(2003 to 2006) to 24.6% (2007 to 2009).
Of the GIST patients who went on to second-line treatments, 73.7% of those used sunitinib as the second-line therapy overall. Only 68% used sunitinib (second-line) from 2003 to 2006 increasing up to 84% use of sunitinib (second-line) from 2007 to 2009. Over the entire study period, 18.8% of patients received second-line drugs; however, there was an actual decrease in patients who went on to receive a second-line drug (22% in the years 2003 to 2006 and only 14.6% from 2007 to 2009).
Of the total GIST patients studied, only 5.9% overall went on to receive a third-line therapy. Third-line drug of choice was nilotinib for 44.4% and sorafenib for 38.9%. However, again changes are seen when analyzed by the years. From 2003 to 2006, 50% of GIST patients were place on sorafenib (third-line) while 63% (third-line) were placed on nilotinib from 2007 to 2009. As might be expected, more patients went on to receive third- line treatments in 2007 to 2009 versus the earlier years of 2003 to 2006.
Less than 1% of GIST patients went on to receive a fourth-line treatment with 66.7% receiving sorafenib for that fourth- line drug option. The duration of treatment time on each drug decreased as more options in drug choices became available over the years 2003 to 2009.
Comment from Phyllis: GIST treatment is very fluid and changing constantly, patients need to stay up to date on new drugs available, look at trends in treatment, and discuss this information with their medical team. While the first study above discussed surgery in the treatment process minimally, the next abstract, discusses the role of surgery more extensively.
Abstract 10550 The role of surgical resection following imatinib treatment in patients with metastatic or recurrent GIST.
Although surgical resection of primary GIST is potentially curative, surgery, but the benefit of surgical resection of GIST metastases combined use of imatinib versus using imatinib alone in patients with metastatic or recurrent disease has not been proven. This study involved 134 patients with metastatic disease. 42 GIST patients received surgical resection of residual lesions after imatinib while 92 GIST patients used imatinib only after diagnosis with metastatic or recurrent GIST.
The patient and tumor characteristics were similar in this study and adjustments were made as scientifically needed in the outcome analysis as well.
The group undergoing surgical resection of residual lesions after imatinib showed significantly better (over double) outcome in progression free survival: 88.7 months versus 42.8 months. Overall survival showed significant benefits of utilizing surgical resection instead of imatinib alone as well.
This study obviously suggests that surgical resection of residual lesions in combination/ after disease control with imatinib may be very beneficial to GIST patients with metastatic or recurrent GIST.
Note from Phyllis on abstract 10550:
This study merits strong consideration for GIST patients and their medical team in planning and discussing future possible treatment protocol for GIST metastatic disease. Patients with wild type GIST that may not be on imatinib at all as adjuvant therapy should certainly note this study.
Abstract #10537 Does a diagnosis of GIST predict a second primary cancer?
This study , while alarming in its title, really does not tell us any alarming information, but rather information that most of us as a GIST patient or GIST caregiver should simply be aware of. We know that GIST and other cancers can make one more susceptible to other cancers due to increased exposure to radiation in scans and a variety of other reasons.
This study is being reported simply to make the GIST patient aware of a few of the specifics of the abstract.
The study was retrospective and looked at 1291 patients. The study found that both sexes had a higher chance of kidney cancer after GIST and that females had a higher chance of colon cancer.
Older age and high grade GIST were associated with the higher malignancy.
Note from Phyllis on abstract 10537:
GIST patients might want to be careful to follow general recommended screenings for kidney cancer and for colon cancers.
GIST patients that have to already see so many doctors and attend so many appointments might be tempted to skip the annual colonoscopy recommended after the age of 50. This study suggests that keeping all of those basic screening type tests and not postponing due to "appointment burnout" is important for all non -GIST related medical needs.
Abstract # 10547 The influence of Gastrointestinal resection on sunitinib exposure in patients with GIST
This study seeks to determine the effect of surgical resection on the absorption of sunitinib and its active metabolite SU12662. With both of the oral chemo drugs imatinib and nilotinib, it has been shown that gastrectomy can reduce drug exposure.
This study involved 305 patients and was subdivided into 6 groups:
1. major gastrectomy
2. partial gastrectomy
3.small bowel resection
4. both gastrectomy and small bowel resection
5. colon resection
6. controls (patients with no prior surgery)
Gastrectomy did not affect sunitinib exposure showing that sunitinib does not critically need the stomach for the dissolution and absorption of the drug. Patients with both a gastrectomy and a small bowel resection did show a significant decrease in total sunitinib exposure. The amount that the resection of the small bowel decreases the sunitinib exposure depends specifically on how much length of the small bowel had to be removed surgically. Therefore, having a resected intestine does not always mean that the sunitinib exposure will be decreased in the clinical setting if the removed amount of intestine is small.
Note from Phyllis on abstract #10547
GIST patients with surgical resection should be aware of the way the current oral chemotherapy drugs will be absorbed into their bodies depending on the specific drug being considered for therapy.
Gene Fusion in Wildtype GIST
While there have been no poster presentations or discussions specific to wildtype GIST so far this year at ASCO 2013, there is one electronic-publication-only abstract (abstract e21523) that shows evidence of gene fusions in GIST. This reinforces the newer discovery methods in tumor analysis, and the need for more aggressive and consistent testing of wildtype tumors to further research, discoveries, and develop the best treatment plans for wildtype GIST patients.
Since the National Institutes of Health wildtype GIST clinics began in 2008, new discoveries have allowed us to now be aware of additional testing that should be done on all tumors in areas such as determining molecular events, mutations, gene sequencing needs/results. Learning more about the next generation gene sequencing approach and its potential help in determining the key to understanding wildtype GIST tumor is vital.
For more on next generation sequencing visit this link:
Oral Mucositis (sore mouth)
Many GIST patients suffer from mouth pain and sores or oral mucositis as a side effect while taking several of the current oral chemotherapy drugs. Two of the more common drugs causing this specific side effect are sunitinib (Sutent) and regorafenib (Stivarga). The mouth sores often coincide with the side effects of hand-foot syndrome as well. Side effects are often severe enough that patients stop taking the drug temporarily or even permanently. The mouth sores affect eating, drinking, speaking, swallowing, and sleeping due to the associated pain.
At ASCO 2013, a company named Helsinn located in LUGANO, SWITZERLAND provided a book published by Springer Healthcare that addresses the issue of mouth sores:
Pocket Books for Cancer Supportive Care: Oral Mucositis by Stephen T. Sonis.
In addition Helsinn has developed a new product, Gelclair (see www.gelclair.net) for use with cancer patients on chemotherapy. Gelclair is a PVP- based viscous oral gel that forms a protective film to help relieve pain and calm mouth lesions.
The company claims that relief is prompt, reducing the severity of the mouth mucositis with use of Gelclair by one grade of severity in only 3 days. While many various "magic mouthwashes" have been developed and used by GIST patients in the past, this new product is one that is worth investigating further for use with our GIST patient population.
When visiting the site of gelclair.com , it states that you can order the product directly from them if in the United States; however, just recently one company has secured the rights to be the USA distributor for the specialized product.
Here are 2 links discussing this new agreement:
Interestingly enough, DARA is located in Raleigh, NC about 2 hours from my home. I will contact David J. Drutz, MD, DARA's chief executive officer and chief medical officer and request more information, a meeting, and investigate the possibility of obtaining samples for our GIST Support International community in order to allow us to test this new product just being released in the USA.
I am hoping that this new product might bring more effective relief of mouth sore pain to our GIST community!
Patient Advocacy Groups
While examining the listing of exhibitors at ASCO 2013, several fellow patient advocate organizations caught my attention. As the representatives at ASCO for GIST Support International, Nancy Berezin and I stopped by several booths and obtained information that may be of benefit to many reading these postings. At GIST Support International, we certainly try to provide education, information, and support! I am glad to be able to share information about some other helpful organizations that are not GIST specific but have services that the GIST patient can certainly use.
My Life Line
The first exhibitor that we met with was My Life Line.
MyLifeLine.org has a mission to support patients as well in a very focused and specific way by allowing patients/families to set up a customized web site of their own via this site. Marcia Donziger is the founder and chief mission officer of this organization. My Life Line has a site similar to others such as care pages.com or care bridge.com ; however, on my life line, several additional features make this site one to consider using.
You can, of course, communicate with family and friends inviting them to be a part of your website for updates on your status medically and otherwise. You can also customize your web site to include links to teach others about your disease. You could link back to GIST Support International, for instance.
A very useful and attractive feature is that you can add a Helping Calendar to show dates and times that people are already providing meals for you after just returning home from a recent hospitalization and allow others to sign up for still needed and available times for meals, help with cleaning, errands, or any needed service that friends and family so want to help out with in times of need.
Visit the site if you are interested in learning more at www.mylifeline.org and click on the right side of the home page to take a patient tour to give you more insight to what this program offers.
Another organization that had an interesting service for GIST patients was the booth for Imerman Angels. Their web site is : www.imermanangels.org
They provide 1-on-1 cancer support to provide personalized connections among cancer fighters, survivors, and caregivers. Jonny Imerman, diagnosed with testicular cancer at the age of 26, founded this group based on the belief that no one should have to fight cancer alone and without the necessary support. Just as our smaller wildtype GIST LISTSERV tends to be a cyber family support group, this site wants to create a very personal link among a current newly diagnosed cancer patient and a seasoned patient and/or cancer survivor.
I thought some on our group might be interested in volunteering to be an individual mentor, and I also thought that many would benefit in being linked with someone directly who also has GIST.
You can request a GIST cancer mentor or a GIST cancer caregiver mentor at their web page.
You can also sign up to be a patient mentor or a caregiver mentor.
If interested in learning more simply visit : www.imerman angels.org
I will be trying to continue a future relationship with these two organizations!