New Horizons GIST Annual Conference (1-3 Oct 2017)
Report by Dr Nikhil Guhagarkar FOM Volunteer
New Horizons GIST is an annual conference dedicated to the latest advances of GIST and it’s advocacy work. It is attended by GIST specialists, pharma company representatives and patient advocates from across the world. It was held from 1-3 October 2017 @ the Life Raft Group Headquarters in New Jersey USA.
Sara Rothschild, of Life Raft group welcomed the delegates and thanked the sponsors of the meet. Norman Scherzer and Michelle Durborow of the Life Raft Group presented the survey results from the Global GIST community.28 countries participated in the survey. A large segment of people said Mutational analysis was still not a standard care in their country this even included some developed countries.
Barriers to access care included Distance, finance, fear of physician and lack of GIST specialist. Imatinib was the easiest accessed drug, while Sunitinib and Regorafenib access was not so easy. Access to trials was difficult in many countries. There were issues of lack of reimbursement of the above drugs.
3 most important things that patients care about in the management of GIST were:
Access to GIST specialist
Access to 2nd, 3rd line of treatment and clinical trials.
Topics like access to correct information, compliance to medication were discussed. It was widely acknowledged the importance of global community network to share resources and do advocacy for the management of GIST.
Dr Suzanne George of the ‘Dana Farber Cancer Institute’ presented on the Emerging therapies and trials. Key points of her talk were:
Imatinib remains the main drug of choice for the treatment of GIST has excellent inhibition for Exon 11 mutation and less for Exon 9 and resistance develops due to secondary resistance KIT mutation.
Sunitinib is a 2nd line of drug has a broader spectrum of cover including Exon 9,11,13,14 & VEGFR challenges and secondary resistance KIT mutation and toxicity.
Regorafenib is a broad inhibitor and the 3rd line of agent effective against Exon 11,17 and VEGFR, Secondary resistance and toxicity.
Due to secondary resistance disease control has remained a challenge and alsotoxicities of some drugs.
Two ongoing trials of new drugs for GIST include:
BLU –285 works against Exon 17/18, DA 42V mutation
Phase 1 study of 72 patients the same was carried out with dose escalation. Optimal dose is 400mg/day. Mostly patients with resistance to Imatinib and other drugs were included in this trial.
PDGFRalpha D842 mutant GIST responded well with dramatic shrinkage of the tumour.
Side effects of BLU-285 are nausea, vomiting, fatigue, diarrhoea, oedema.
Recommended dose is 400 mg once a day.
Phase 3 study is underway and results are awaited to this new promising drug for GIST.
Useful for exon13/14 and 17/18
Phase 1 dose escalation study done upto 400mg given 200 mg bid, drug being well tolerated with minimum side effects.
Showed good disease control in resistant GIST cases. It is going into phase 3 trials across the world.
Dr William Tapof ‘Memorial Sloan Kettering Cancer Centre’ talked on the Advances in the treatment of GIST.
He talked on the history of GIST treatment, Glivec it’s efficacy and reason for resistance including different mutations. Sutent sometimes acts better as it is a smaller molecule and binds to the ATP binding pocket site better. Resistance can be polyclonal that is multiple mutations in different sites of the same tumour.
He stressed on the importance of Mutational analysis for precision medicine treatment.
PLX3397Useful for Exon 13+14 + Imatinib combination hits some sites of receptors hence better control.
PLX9486 Is useful for mutations Exon 17+18 is used in combination with Sutent useful for
Understanding Immune microenvironment of Sarcomas: M1 macrophage inhibits tumour growth.
M2 macrophage helps tumour growth, drugs are being developed to inhibit M2 to reduce the tumours. Glivec helps in the same.
Combination of Checkpoint Inhibitor and TKI works well
Imatinib potentiates antitumor T cell responses in GIST through inhibition of IDO
ETV1 inhibition is equally important as KIT inhibition to control GIST.
MEK162 in combination with Imatinib is been used in a trial for wild type of GIST.
Dr Ciara Kelly of ‘Sarcoma medical oncology services’ talked on Liquid Biopsy.
Detecting CT DNA of tumour DNA, In the process of Liquid biopsy blood is drawn in Streck tube which causes plasma separation. From where Cf DNA is extracted & quantified.
Ct DNA as a bio marker in GIST can be used in 3 ways:
1.Predictive-quantify the tumour to respond to a specific therapy.
2.Pharmacodynamic-provides dynamic assessment and biological response to treatment.
3.Discovery– Identifies aberrations and resistance to treatment. Helps identify secondary KIT mutations.
Role of Ct DNA in GIST is:
1.Localised disease: Detecting risk of recurrence, Therapeutic selection.
2.Metastatic disease: therapeutic selection & monitoring response to therapy.
3.Refractory disease: detection of mechanism of resistance, appropriate therapeutic selection in timely fashion, capturing tumour heterogenicity and subclone-specific response.
Key is to match the results of mutational analysis of biopsy sample and the analysis of Ct DNA, sometimes plasma DNA has showed more mutations in a patient.
Ct DNA is a good potential of bio marker of response
In the Neo adjuvant setting it can be used for determine optimal time to resection.
In the Adjuvant setting it could help response and effectiveness and duration of therapy.
In the Metastatic setting it can facilitate treatment decisions in a timely fashion.
In monitoring response to therapy patients with larger tumours were having more volume of Ct DNA as compared with patients having better response to treatment.
Detection of minimal residual disease. Presence of Ct DNA in large quantity indicates progressive disease and more chance of recurrence and lesser Ct DNA indicates minimal chance of recurrence.
Ct DNA potentially can detect recurrences before imaging can detect.
Liver disease can be detected better than peritoneal disease.
Economics short term it will cost more, long term it will be cost effective replacing tissue biopsy and better monitoring of response.
Conclusion: ctDNA has a potential of being a blood biomarker of clinical and molecular behaviour of
Further development is required sequencing technology is improving sensitivity of detection.
Routine collection of ctDNA in GIST trials is important to take this techonology forward.
It can detect resistance better and guide therapeutic selection.
Dr Kelly, Dr Tap & Dr Suzzane presented various cases of GIST, including traditional therapy like Neo-adjuvant to Surgery to Adjuvant therapy with good control while some were of resistant cases which required multiple drugs like Imatinib, Sunitinib, Regorafenib to drug trials with Blu-285, DCC -2618 and many others.
Importance of Neo adjuvant therapy to shrink the tumour and cause a lesser invasive surgery and hence preservation of normal tissues causing lesser morbidity and mortality was emphasised.
Importance of Mutational analysis was stressed to give precision medicine for better response of therapy. In some refractory cases Immune therapy was tried.
A discussion on Real World Data was done by a panel.
The topics included were since the year 2000 patient survival has increased since the introduction of Imatinib and other drugs.
Molecular testing is being made mandatory in most places.
Being a rare cancer the number of patients available for drug trials and data is less, being a long term treatment compliance is an issue. Need for GIST specialist is emphasised.
Clinical trials of 2 drugs of different pharma companies is a challenge due to inter personal pharma issues.
Life Raft real world evidence platforms are:
. Patient registry and tissue bank.
Rodrigo Salas talked on real life data collection in Mexico. Dr Suzanne George talked on Data informs clinical guidelines. Dr Theresa of ‘FDA’ talked on Patient-focussed drug development: indentifying and building needed data sources to integrate patient perspective in decision making. Dr Carl Asche talked on Evaluation of health care Interventions and big data. Michelle Durborowof Life Raft talked on their new GIST Primean patient powered GIST registry aimed at collecting real world data on GIST like Diagnosis, Medication, Surgery, Compliance.
Pat Garcia-Gonzalez, CEO of The Max Foundation talked on “Access to GIST treatment in Low and Middle income Countries: The Good, the Bad and the Ugly”
The Max Foundation GIST strategy: Aims to decrease premature mortality from GIST in neglected populations of the world through humanitarian access to treatment, care and support
Facts of GIPAP program:
.Since 2001 Novartis has provided access to Glivec through GIPAP to more than 11,000
.Currently more than 3,300 GIST patients are still in GIPAP (4 GIST patients have been in GIPAP since 2002)
.On average we approve 800 GIST patients every year in GIPAP: 500 of these have unresectable/metastatic GIST and 300 have adjuvant GIST
.34 countries have only 1 physician who treats GIST
.GIST patients represent 10 percent of the GIPAP population
CMLPath to Care™ collaboration replaces GIPAP with a new, independent, patient-centered access model as a Max Access Solution
In the Good of the program Pat talked on collaboration with various pharma companies and their support for GIST patients.
In the Bad she talked on different problems in various countries like Government apathy, Socio economic problems, no access to GIST specialist, no insurance cover.
In the Ugly she talked on numerous African countries with absolute no access to treatment.
Pat called on the need to better the above situations and provide good access to treatment for all GIST patients.
Gerard van Oortmerssenfrom Netherlands talked on the patients forum: Telling the Patient story and its impact on healthcare. He talked on his own unique software for GIST patients whereby they can search for various aspects of GIST including side effects, dosage , support etc.
Amy Bruno-Lindner of Austria spoke on Improving Patient Advocate – Patient communication: Principles and Techniques.
Which was based on 3 things :
.Giving Empowerment to the patients.
She talked on keeping it simple to the patient and using Analogies like:
“KiT is like a gas pedal, Mutant KIT GIST is like a stuck gas pedal”
“Imantinib fits like a key in a lock”
“Metastasis are like seeds of Dandelion”
“Cystic transformation of GIST tumour makes it looks like hole in swiss cheese”
Also it is important to empower patients with the right knowledge like Clinical trials are not making them lab experiments but giving them cutting edge drugs.
The role of a Patient advocate in sharing the right information, having Empathy with patients problems and Giving solutions to empower patients is highlighted.
Round table meetings took place between groups on various topics to offer solutions to global problems in developed and developing countries.
Geoffrey Cook of Novartis gave an insight into his company and the new drugs it is bringing out in the market including Immune Therapy Drugs and many more.
GIST being a rare cancer it is important to have a large Worldwide data about the disease, efficacy of the drugs used in the treatment and other factors like having a Tissue bank for more research on the mutations and new drug development.
GIST Prime and SideEq are wonderful new patient powered websites.
BLU-285, DCC-2618 are new drugs on trials now which are showing a promise for better response in resistant GIST.
Newer drug trials should be conducted to find better drugs.
Drug combinations are also known to work in patients with resistant/multiple mutations.
Liquid biopsy is a fast emerging Bio marker in GIST, is lesser invasive and is used for diagnostic, monitoring response, detection of multiple mutations. It needs more fine tuning before becoming the main stream in the treatment protocol for GIST.
Patient support organizations are important for the support of the patients to give them information, hope and empower them!
It is important for the Global GIST community to work closely and share resources and research in getting cure for GIST.