Jonathan C. Trent, MD, PhD, professor and associate director for Clinical Research at the Sylvester Comprehensive Cancer Center, University of Miami Health System, discusses the role of avapritinib (Ayvakit) in 

 exon 18–positive gastrointestinal stromal tumor (GIST). 

 for the treatment of adult patients with unresectable or metastatic GIST who harbor a 

Prior to the approval, findings from the randomized phase 3 VOYAGER trial failed to demonstrate a survival benefit with avapritinib vs regorafenib (Stivarga) in patients with locally advanced, unresectable or metastatic GIST. However, data from the phase 1 NAVIGATOR study showed an 84% overall response rate with avapritinib in patients with 

 exon 18–mutant GIST is resistant to all other available TKIs for patients with GIST, so the approval of avapritinib filled a significant unmet need for this specific patient population, says Trent. Moreover, the efficacy demonstrated with avapritinib was similar to that demonstrated with imatinib (Gleevec) in patients with 

Videos

Jonathan C. Trent, MD, PhD, discusses the role of avapritinib in PDGFRA exon 18–positive gastrointestinal stromal tumor. 



Dr. Trent on the Role of Avapritinib in PDGFRA Exon 18+ GIST 

Jonathan C. Trent, MD, PhD, professor and associate director for Clinical Research at the Sylvester Comprehensive Cancer Center, University of Miami Health System, discusses the utility of circulating tumor DNA (ctDNA) to understand primary driver mutations in gastrointestinal stromal tumor (GIST).

ctDNA testing is noninvasive and has a rapid turnaround time of about 1 week, explains Trent. The results of ctDNA testing can shed light on primary driver mutations, as well as resistance mutations that could arise following treatment with imatinib (Gleevec). 

GIST comprises about 10 subtypes with different driver mutations, including 

, and succinate dehydrogenase deficiency, Trent says. Understanding what mutation is driving the disease can inform treatment selection for patients, Trent explains. For example, patients with 

-driven GIST will benefit from a RAS inhibitor rather than a KIT inhibitor, Trent concludes.

Jonathan C. Trent, MD, PhD, discusses the utility of circulating tumor DNA to understand primary driver mutations in gastrointestinal stromal tumor.  



Dr. Trent on the Utility of ctDNA to Understand Primary Mutations in GIST 

Jonathan C. Trent, MD, PhD, professor and associate director for Clinical Research at the Sylvester Comprehensive Cancer Center, University of Miami Health System, discusses the potential role of immunotherapy in gastrointestinal stromal tumors (GIST). 

Immunotherapy has demonstrated limited utility in patients with GIST, says Trent. A study from 2012 showed promising clinical outcomes with the combination of imatinib (Gleevec) and peginterferon α-2b in patients with GIST. The combination appeared to activate some immune cells in biopsied GIST tissue; however, the patient population size was limited, Trent says.

Additionally, the combination of ipilimumab (Yervoy) and nivolumab (Opdivo) has elicited responses in patients with heavily pretreated GIST, Trent explains. Although immunotherapy has shown early efficacy signals in GIST, doublet or triplet strategies are likely needed to activate the immune system against GIST cells, concludes Trent.

Jonathan C. Trent, MD, PhD, discusses the potential role of immunotherapy in gastrointestinal stromal tumors.  


Dr. Trent on the Potential Role of Immunotherapy in GIST 

Jonathan C. Trent, MD, PhD, professor and associate director for Clinical Research at the Sylvester Comprehensive Cancer Center, University of Miami Health System, sheds light on the impact of COVID-19 on the treatment of rare cancers.

Please visit 

 to watch the entitreity of the MJH Life Sciences News Network, which provides the latest news across a variety of healthcare specialties, and a number of interviews with experts in the medical field, many of which are focused on the ongoing 

Jonathan C. Trent, MD, PhD, sheds light on the impact of COVID-19 on the treatment of rare cancers.

Dr. Trent on the Impact of COVID-19 on the Treatment of Rare Cancers

Jonathan C. Trent, MD, PhD, professor and associate director for Clinical Research at the Sylvester Comprehensive Cancer Center, University of Miami Health System, discusses research efforts in bone and soft tissue sarcomas.

Recently, several advances have been made in the field of research for bone and soft tissue sarcomas, says Trent. Notably, immunotherapy is becoming useful in the management of certain types of patients with certain types of sarcomas. For instance, a recent publication in the Lancet Oncology showed that patients with alveolar soft part sarcoma may benefit from immunotherapy with a checkpoint inhibitor plus a receptor TKI.

In the single-center, single-arm, phase 2 trial, investigators assessed the activity of the VEGF receptor TKI axitinib (Inlyta) plus pembrolizumab (Keytruda) in patients with sarcoma. With a median follow-up of 14.7 months (IQR 10.1-19.1), 3-month progression-free survival (PFS) for all evaluable patients was 65.6% (95% CI 46.6-79.3). For patients with alveolar soft part sarcoma, the 3-month PFS was 72.7% (95% CI 37.1-90.3). Investigators reported a 50% partial response rate, which is remarkable for a disease that is known to be resistant to chemotherapy, concludes Trent.

Jonathan C. Trent, MD, PhD, discusses research efforts in bone and soft tissue sarcomas.
 
 

Dr. Trent on Research Efforts in Bone and Soft Tissue Sarcomas

Associate Director, Clinical Research Sylvester Comprehensive Cancer Center

This scenario is familiar to oncologists at cancer centers around the world: A patient with advanced cancer requires a precision medicine test, such as next-generation sequencing (NGS), for optimal management. The physician fills out a paper form, which is then faxed to a vendor. After receiving the fax and routing it to the right individual, requesting tissue, obtaining tissue, and performing NGS, the vendor faxes or e-mails the results to the doctor’s office. The fax or the printed e-mail is often scanned into the patient’s electronic medical record (EMR) or placed in the paper record.

Needless to say, this approach is slow, inefficient, and archaic. The EMR folder is already overflowing with other data that are often not organized in an easily searchable format. At times, tracking down the NGS results is a test of endurance. This entire process is laden with manual exchanges and time-consuming printing and scanning that substantially delay care for patients with cancer, who clearly do not have time to waste.

To better manage this challenge, Sylvester Comprehensive Cancer Center, part of the University of Miami Health System, initiated a partnership with Syapse, a company that specializes in precision oncology solutions. With Syapse, we have been able to streamline the precision medicine process and organize the data to improve care for our patients with cancer.

The most obvious benefit from this partnership with Syapse is easy access to critical precision medicine data. Syapse has created a secure electronic portal between vendors and our EMR that is compliant with the Health Insurance Portability and Accountability Act. Our updated version of the precision medicine workflow is not only more efficient, it improves turnaround time for test results.

Physicians and patients decide to pursue NGS. The physician enters the patient’s chart in the EMR and not only chooses specific tests but also selects the vendor to perform testing from user-friendly dropdown menus. The system automatically notifies our pathology laboratory to obtain the patient’s archival tumor samples and provides the tissue to the testing vendor in a timely fashion.

After the testing is complete, the vendor sends the results through an electronic portal directly to the patient’s chart in the EMR. An automated, electronic notification is sent to the physician or designee when the test results are available. When the patient returns, the provider can open the patient’s record and easily find the new testing data, which are searchable and annotated by vendor and test type.

This approach eliminates a number of barriers that often unacceptably delay patient care. By placing all the test data in the patient’s EMR, physicians no longer need to access multiple vendor sites, with multiple passwords. Also, removing the manual handling associated with faxes and e-mails enhances speed and reduces human error.

Rapid access to precision medicine data is necessary for optimal patient care and drives important opportunities that could potentially advance our understanding of cancer.

This new, digital process supports a wide range of clinical investigations. Discrete precision medicine results enhance data mining so that we can identify patients within the EMR whose tumors harbor specific mutations. This allows for seamless collection and analysis of clinical outcomes and fosters the development of biomarkers that allow continuous improvement in patient care.

The Syapse platform ensures our ability to rapidly and easily study patients who have received precision medicine tests. Early results from these types of investigations have been quite positive.

In our experience, approximately 30% of patients had their treatment modified or a new therapy recommended because of precision medicine results. In some cases, patients with no other options were enrolled in clinical trials. Fast access to precision medicine results made these care improvements possible. The platform also gives us important data to drive clinical trials. We are able to prospectively identify patients in our health system who are likely to benefit from a therapy that matches their specific molecular abnormality.

Sylvester Comprehensive Cancer Center is a tertiary referral center, which means we treat patients from the southeastern United States, Latin America, and the world. As a result, our clinicians see quite a few patients with gastrointestinal stromal tumors (GISTs). The majority of these patients have mutations in the 

 mutations. Because we have so much granular data on this mutation in these tumors, we are able to treat patients with 

-mutant GISTs with RAF inhibitors rather than the more commonly prescribed imatinib, which is only active against 

-mutant GISTs. This is such a tiny subgroup, we never could have designed a full-fledged clinical trial.

The partnership with Syapse is only one aspect of the investment Sylvester has made in upgrading our infrastructure. Another example is our precision medicine tumor board.

In many ways, the tumor board provides the multidisciplinary processing so necessary for excellent cancer care. Precision medicine test results, medical history, treatment history, pathology, radiology, and many other factors are evaluated by the group’s combined expertise. Molecular pathologists join medical, radiological, surgical, gynecological oncologists, and others to fully analyze an individual patient’s data to determine the best therapeutic approach for each patient.

These meetings guide treatment and compile evidence to help patients into clinical trials or off-label therapy, or petition a drug company for a compassionate-use waiver.

Even more exciting is the precision medicine clinic that was created to help patients understand their disease and how its unique molecular fingerprints can guide therapy. By introducing patients to the strange new language of precision medicine, we increase their comfort levels and help them make informed decisions about their own care.

We have entered a promising new era of precision medicine, but we have to move beyond theoretical constructs to proven approaches. The only way we can do that effectively is to have access to the data.

Our recent partnership with Syapse, and other refinements, have made that a reality, and early results have been encouraging. Finally, we are leveraging NGS and other molecular data to design trials that target the aberrant proteins found in the tumors that are prevalent in our patient population.

Articles

Jonathan C. Trent, MD, PhD, discusses Sylvester Comprehensive Cancer Center’s ongoing efforts to advance the precision medicine process to improve patient care.

Streamlining the Precision Medicine Process: It's Possible, Necessary, and Improves Care

Jonathan C. Trent, MD, PhD, professor of medicine, Sylvester Comprehensive Cancer Center, University of Miami Health System, discuses a phase II study of pembrolizumab in advanced sarcomas,

There were several abstracts presented at the ASCO 2016 Annual Meeting that focused on immunotherapy in sarcoma. One of the most interesting looked at SARC028, a phase II study of the anti-PD-1 antibody pembrolizumab in patients with advanced sarcomas, said Trent.

The overall objective response rate 19% and the disease free rate at 4 months was 44% compared to a historical control of 20%. Thirty-three percent of patients with undifferentiated pleomorphic sarcoma, and dedifferentiated liposarcoma treated on this trial had a reduction in tumor size.

This clearly shows that  pembrolizumab has activity as a single-agent, said Trent. There is future potential to use it in combination in sarcoma as well, he said.

Dr. Jonathan Trent on Pembrolizumab in Advanced Sarcomas

Jonathan C. Trent, MD, PhD, professor of medicine, Sylvester Comprehensive Cancer Center, University of Miami Health System, discusses T-cell therapies in sarcoma.

Many types of sarcomas have translocations and point mutations that lead to novel antigens that can be specifically recognized by an engineered T cell, says Trent.  

There are also several types of sarcoma, such as synovial sarcoma and liposarcoma that express testicular antigens—such as NY-ESO-1&mdash;that are not expressed in any other cell in the human body. These neoantigens can be targets of modified T-cells, such as the T-cells that are now being engineered by a number of different companies to bind to and kill NY-ESO-1 in synovial sarcoma and liposarcoma cells.

Clinical trials are available investigating these agents.

Dr. Jonathan Trent on Engineered T- cell Therapy in Sarcoma

	University of Miami Miller School of Medicine

Determining the best course of treatment for sarcomas of the bone and soft tissues is a complex process. Clinicians have identified more than 100 different types of sarcomas such as gastrointestinal stromal tumors (GISTs), as well as benign tumors such as desmoid fibromatosis, chordoma, giant cell tumors of bone, or pigmented villonodular synovitis. Because making an accurate diagnosis is essential to developing effective personalized treatment strategies, practice guidelines from the National Comprehensive Cancer Network call for patients with sarcoma to be evaluated at sarcoma centers with experienced, multidisciplinary teams.

The Bone and Soft Tissue Sarcoma Program at the Sylvester Comprehensive Cancer Center— South Florida’s only Cancer Center of Excellence&mdash; provides an example of how this patient management approach can be put into practice, leading to better outcomes. Each year, our team sees more than 600 new pediatric, adolescent, and adult cases, serving as a vital resource for patients from throughout the United States, the Caribbean, and Latin America.

A typical patient journey begins with a phone call from a patient or referring physician to the sarcoma nurse navigator, who gathers information and organizes the process.

The first step involves appropriate imaging. A musculoskeletal radiologist may identify unique imaging features on CT or MRI scans that suggest sarcoma. Together, the radiologist and orthopedic oncologists determine the best approach for a biopsy.

An accurate biopsy is vital. A mistake in the biopsy approach can lead to contamination of surgical planes, necessitating a more extensive surgery or even higher risk for recurrent disease. Biopsy material and any archival tissue from outside institutions are then forwarded to our board-certified pathologist, Andrew E. Rosenberg, MD, chief of Anatomic Pathology, and director of the Bone and Soft Tissue Service. Dr Rosenberg has extensive experience in diagnosing musculoskeletal neoplasms and metabolic bone disease.

At this juncture, additional molecular or immunohistochemical analysis is employed to make every effort to subtype the sarcoma. At Sylvester, the diagnostic process includes molecular analysis of tumor tissue for mutations, translocations, amplifications, or deletions. These additional analyses can drastically alter treatment plans.

For example, Dr Rosenberg played a pivotal role in describing a gene mutation in the isocitrate dehydrogenases (IDH) enzyme and discovering that it expressed very frequently in chondrosarcoma.

With that finding, our researchers have been studying the mutation in chondrosarcoma cell lines in the lab and have partnered with industry to conduct the first clinical trials of IDH inhibitors. Now, all suspected chondrosarcomas are submitted for IDH testing up front so that patients with this mutation may be offered clinical trials of IDH inhibitors, if appropriate, for the current disease stage.

Another example occurs in patients with GIST, the most common sarcoma of the GI tract. All patients are tested for the KIT gene mutation at diagnosis. If the mutation is in the exon 11 region of that gene, we treat it with 400 mg of imatinib aday. If the mutation lies in the exon 9 region, we treat the patient with 800 mg a day.

Additionally, other mutations have been identified that predict resistance to imatinib and support enrollment in other clinical trials, saving the patient from unnecessary and ineffective treatment. Ten years ago, medical oncologists did not have the capability to inhibit these gene mutations that are driving the cancers.

Sylvester, which is part of UHealth—University of Miami Health System and the University of Miami Miller School of Medicine, can draw on the knowledge of professionals throughout the academic medical center in treating patients with sarcoma. Our core 15-person multidisciplinary team holds a sarcoma conference twice a week to evaluate the management of current patients and discuss optimal treatment strategies for new patients.

Our medical oncologists, pediatric oncologists, radiation oncologists, surgical oncologists, musculoskeletal radiologists, and pathologists may use chemotherapy, surgery, or radiation therapy, depending on the individual case. The prospective treatment options include:

		Preoperative chemotherapy, targeted therapy, or immunotherapy, which can dramatically improve surgical outcomes, guided by a sarcoma medical oncologist

		Preoperative radiation therapy by a sarcoma radiation oncologist

		Resection of primary and/or metastatic sarcoma by an orthopedic, surgical, head and neck, genitourinary, or gynecologic sarcoma oncology specialist

		Postoperative chemotherapy, targeted therapy, or immunotherapy to decrease the risk of recurrent disease, by a sarcoma medical oncologist

		Follow-up visits with a sarcoma medical oncologist

In developing a treatment plan, it is also important to consider the psychosocial issues facing an individual patient. For example, adolescents and young adults with sarcomas are likely to have deep concerns about their fertility, education, and careers. Having a social worker and health system navigator on the sarcoma team can provide both patients and family members with needed support.

Additionally, Sylvester has an accomplished psychiatry/psychology division through the Courtelis Center, specifically focused on treatment of mental illness and adjustment problems that are common in patients undergoing cancer therapy.

At Sylvester, well-designed, patient-relevant research studies are incorporated into our discussion of treatment options, including clinical trials for newly diagnosed cases as well as for metastatic or recurrent sarcomas.

Our portfolio includes cooperative group studies, industry-sponsored studies, and investigatorinitiated studies. Additionally, as members of the Sarcoma Alliance for Research through Collaboration (SARC), our oncologists can serve as a liaison for patients to clinical trial opportunities elsewhere in the international sarcoma community.

		Figure. MRI Images of a 48-year-old Firefighter With High-Grade Pleomorphic Myxofibrosarcoma

		The tumor dramatically decreased in size and enhancement after six cycles of preoperative doxorubicin/ifosfamide chemotherapy and preoperative radiation, permitting a complete resection and removal of 100% necrotic tumor without damage to neurovascular structures.

Currently, there are nearly 20 clinical trials available for sarcoma patients at Sylvester, including two trials for patients with the IDH gene mutation, who currently have no other treatment options. Sylvester has two of the few patients with chondrosarcoma in the world enrolled on IDH inhibitor studies.

Drawing on the “bench-to-bedside” treatment concept, Sylvester’s researchers are focusing on genetics, stem cells, immunotherapy, and other strategies. Whereas immunotherapy has only recently made national headlines, we have been enrolling patients with sarcoma on a highly innovative vaccine protocol for more than a year. After patients undergo surgery, their dendritic cells are harvested and incubated in the lab with protein lysates isolated from the patient’s own tumor to make personalized vaccines. The “educated” dendritic cells and additional tumor protein “boosters” are then administered over the next several months.

Additional trials involving immunotherapy are in the planning stages and will be available in the coming months for patients with sarcoma. Along with investing in sarcoma research, we are building a comprehensive sarcoma patient registry and tissue bank, with the ultimate goal of analyzing the molecular biology of sarcoma cancer cells and using that knowledge to design new treatments.

In the near future, consenting sarcoma patients can have their tumor tissue submitted for sequencing, to detect the “mistakes” in the genetic code driving the tumor growth. Any identified mistakes may be used to direct patients to clinical trials specific for those abnormalities. Additionally, these data will be collected and maintained in the sarcoma databases for future analysis.

Jonathan C. Trent, MD, PhD, is co-director of the Musculoskeletal Center, Sarcoma Medical Research Program at the Sylvester Comprehensive Cancer Center, and professor of Medicine, University of Miami Miller School of Medicine. He serves as editor of The GIST Cancer Journal.

Breelyn A. Wilky, MD, is an oncologist in the Sarcoma Program at the Sylvester Comprehensive Cancer Center, and assistant professor of Medicine, University of Miami Miller School of Medicine. 

Determining the best course of treatment
for sarcomas of the bone and soft tissues
is a complex process.

Jonathan C. Trent, MD, PhD