Breelyn Wilky, MD, is the director of Sarcoma Medical Oncology, The Cheryl Bennet and McNeilly Family Endowed Chair in Sarcoma Research, director of Sarcoma Medical Oncology, and deputy associate director for Clinical Research at the University of Colorado Cancer Center – Anschutz Medical Campus.

Breelyn Wilky, MD, details personalized therapy approaches for the treatment of patients with GIST.

Dr Wilky on the Role of Personalized Therapy in GIST

“You don’t want to put a patient on imatinib and tell them everything’s going to be great—you’re going to review a 90% chance of response. If you don’t [because] you have a patient who is resistant, it could totally change your therapy.”

Breelyn Wilky, MD, the director of Sarcoma Medical Oncology, The Cheryl Bennet and McNeilly Family Endowed Chair in Sarcoma Research, director of Sarcoma Medical Oncology, and deputy associate director for Clinical Research at the University of Colorado Cancer Center – Anschutz Medical Campus, detailed approaches for personalized therapy for the treatment of patients with gastrointestinal stromal tumors (GIST).

Currently, the personalized therapy approaches for the treatment of patients with GIST are still being validated through clinical trials, Wilky began. She explained that approximately 90% of patients with GIST are treated with adjuvant imatinib (Gleevec). In many of these patients, imatinib is the standard, as their tumors have exon 11 or exon 9 mutations, which are sensitive to the agent, she noted. However, the remaining 10% of the population may have mutations that are not sensitive to imatinib, including 

D842V mutations, which are entirely resistant to imatinib, Wilky added. Notably, 

in January 2020, the FDA approved avapritinib

 (Ayvakit) for the treatment of adult patients with unresectable or metastatic GIST harboring 

 exon 18 mutation, including D842V mutations, particularly for this type of imatinib-resistant GIST, she emphasized. The approval of avapritinib was supported by data from the phase 1 NAVIGATOR trial (NCT02508532) that enrolled 43 patients with GIST who harbored a 

 exon 18 mutation, of which 38 patients harbored 

Although this mutation is present in a smaller percentage of patients, it’s important not to tell every patient that all will be fine once they begin on imatinib therapy, Wilky advised. She noted that it’s essential to recognize the possibility of patients with imatinib-resistant disease, which could alter the trajectory of their treatment. When patients are newly diagnosed with GIST, it’s important to complete a mutation test upfront to rule out the 10% of patients who may have resistance to imatinib before starting them on the treatment, she concluded.

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Breelyn A. Wilky, MD, director, Sarcoma Medical Oncology, the Cheryl Bennett and McNeilly Family Endowed Chair in Sarcoma Research, deputy associate director, Clinical Research, University of Colorado Anschutz Medical Campus, discusses the rationale for investigating the combination of zalifrelimab (AGEN1884), balstilimab (AGEN2034), and doxorubicin in patients with advanced/metastatic soft tissue sarcoma, and early results from a phase 2 trial (NCT04028063).

Data from the study presented at the 2023 ASCO Annual Meeting showed that patients evaluable for the study’s primary end point (n = 28) experienced a 6-month progression-free survival (PFS) rate of 46.4% (95% CI, 28%-66%), and the median PFS was 24.4 weeks (95% CI, 23.4-72.9). Among all patients evaluable for efficacy (n = 30), the median overall survival was 63 weeks (95% CI, 50-120).

With the increased use of immunotherapy in other tumor types, researchers remain interested in exploring avenues to use these treatments for patients with sarcomas, Wilky begins. PD-1 and CTLA-4 inhibitors alone may only help a small fraction of patients with sarcomas because these tend to be immune-cold tumors, Wilky expands. Investigators hoped that the addition of chemotherapy with doxorubicin may convert these tumors hot, thereby improving the responses to checkpoint inhibitor therapy, she explains. Findings from the phase 2 trial demonstrated that there were patients who had considerable benefit from this therapy, including those in subtypes that may not normally be expected to respond to checkpoint inhibitors or to doxorubicin, she notes.

Additional data showed the objective response rate was 33.3% (95% CI, 17%-53%) with a disease control rate of 80% (95% CI, 61%-92%). Wilky notes that a change to the trial protocol was made halfway through the study after patients who received priming introductory cycle of immunotherapy before chemotherapy were responding well. Therefore, investigators are now trying to understand whether a priming cycle of immunotherapy is needed before using chemotherapy in patients with soft tissue sarcoma, she concludes.

Breelyn A. Wilky, MD, discusses the rationale for investigating the combination of zalifrelimab, balstilimab, and doxorubicin in patients with advanced/metastatic soft tissue sarcoma, and early results from a phase 2 trial.


Dr Wilky on the Study of Zalifrelimab, Balstilimab, and Doxorubicin in Soft Tissue Sarcoma

Breelyn Wilky, MD, director, Sarcoma Medical Oncology, deputy associate director, Clinical Research, associate professor, Medicine-Medical Oncology, University of Colorado Medicine, discusses the diagnosis and management of desmoid tumors.

Desmoid tumors are a type of soft tissue tumor that often occur spontaneously and are localized to one area of the body, such as the leg, arm, or trunk, Wilky says. Like sarcomas, desmoid tumors are rare, so patients are often misdiagnosed with a bone spur or cyst. As such, it is critical for patients to seek a second opinion from a soft tissue tumor specialist to confirm an accurate diagnosis.

Historically, surgery was the mainstay of treatment for patients with desmoid tumors. However, surgical resection can trigger recurrences of desmoid tumors in up to 50% of patients. Alternative options, such as observation or systemic therapy, should be considered as approximately 20% of desmoid tumors regress without surgical or therapeutic intervention, Wilky explains.

If patients require treatment because they have pain or their tumor is in a potentially life-threatening location, such as the abdominal wall or chest, hormone-blocking agents, traditional chemotherapies, and targeted therapies, such as sorafenib (Nexavar), are potential systemic options, Wilky says. Additionally, novel agents, such as nirogacestat, and interventional approaches, such as cryoablation, are being evaluated to expand the therapeutic paradigm.

Notably, desmoid tumors that occur in conjunction with familial adenomatous polyposis are particularly challenging to manage because patients have an inherited tendency to develop multiple desmoid tumors in multiple areas, such as the abdominal cavity. In these cases, it can be difficult to maximize quality of life as many patients have undergone multiple surgeries and have complications from bowel obstructions or resections. Although the field hopes that novel agents like nirogacestat will be effective in this patient population, this subgroup represents an area of unmet need, Wilky concludes.

Funding from SpringWorks Therapeutics/Content Developed Independently by OncLive

Breelyn Wilky, MD, discusses the diagnosis and management of desmoid tumors.  



Dr. Wilky on the Diagnosis and Management of Desmoid Tumors

	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. 

Articles

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

Breelyn A. Wilky, MD

Articles

Dr Wilky on the Role of Personalized Therapy in GIST

Dr Wilky on the Study of Zalifrelimab, Balstilimab, and Doxorubicin in Soft Tissue Sarcoma

Dr. Wilky on the Diagnosis and Management of Desmoid Tumors

Treating Bone and Soft Tissue Sarcomas