George D. Demetri, MD, director, Center for Sarcoma and Bone Oncology, senior vice president, Experimental Therapeutics, Dana-Farber Cancer Institute, professor of Medicine, Harvard Medical School, discusses the use of larotrectinib in patients with TRK-fusion gastrointestinal (GI) cancers.

Physicians have merged and analyzed the data from 3 studies that examined the use of larotrectinib in patients with TRK-fusions. The results, presented by Dr Michael Nathanson on behalf of the Dana-Farber Cancer Institute and other participating centers at the 2018 World GI Meeting, focused on patients with GI cancers.

The data in GI cancers are very similar to the data across many types of cancers, says Demetri. Virtually all patients had meaningful responses. This includes patients with pancreas cancer, colorectal cancer, and sarcomas of the GI tract. Patients with sarcomas of the GI tract seemed to have the most durable responses, states Demetri.

The study gives oncologists a reason to be on the lookout for patients with TRK fusions, as larotrectinib is likely to be approved by the FDA in the near future.

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Dr. Demetri on Larotrectinib in TRK-Fusion GI Cancers

George D. Demetri, MD, senior vice president for Experimental Therapeutics at the Dana-Farber Cancer Institute, professor of Medicine at Harvard Medical School, and co-director of the Ludwig Center at Harvard, discusses the importance of collaboration in sarcoma.

While there has not really been anything practice-changing recently in sarcoma, there has recently been a coalescing of the continuum of science: from the most basic discovery scientists, who deal with worms and basic mechanisms of DNA and enzymes, all the way up to the most clinical of clinicians, said Demetri.

There is an effort to make a true continuum between the basic scientists and clinical scientists, and the pediatric and adult oncologists in the sarcoma space. The changes in practice could not have happened without the advances in basic science, academic investigators, and the industrialists who are really trying to derive it to practice-changing methods, said Demetri.

Dr. George D. Demetri on the Importance of Collaboration in Sarcoma

George D. Demetri, MD, senior vice president for Experimental Therapeutics at the Dana-Farber Cancer Institute, professor of Medicine at Harvard Medical School, and co-director of the Ludwig Center at Harvard, explains how sarcoma treatment has influenced the treatment of other cancers.

Sarcoma continues to pave the way for what is happening in other cancers, says Demetri. The disease is broken down into over 500 different subtypes, each with their own treatment specifications. This method is now being applied in lung, breast, and colorectal cancers, says Demetri.

Some cancers have also been decommissioned, and are not longer consider carcinomas at all.

Dr. George D. Demetri on the Impact of Sarcoma Subtyping on Other Cancers

George D. Demetri, MD, senior vice president for Experimental Therapeutics at the Dana-Farber Cancer Institute, professor of Medicine at Harvard Medical School, and co-director of the Ludwig Center at Harvard, discusses the evolving and advancing field of sarcoma.

Providing patients with more precise sarcoma diagnoses helps better drive treatment decisions and appropriately matches patients with clinical trials. This mindset has translated into other tumor types, as well, Demetri explains.

Additionally, targeted therapies such as TREK-1 inhibitors are showing promise as a potential treatment for patients with sarcoma. Findings from clinical trials examining immunotherapeutic agents in this patient population are likely to be presented at the 2016 ASCO Annual Meeting, he adds.

Sarcoma is also leading the way in the epigenetic space; for example, subtypes including malignant rhabdoid tumors, synovial sarcomas, and epithelioid sarcomas could be treated with H2 inhibitors. Additionally, the breakthrough therapy designation of the affinity enhanced T-cell therapy is “the tip of the iceberg,” in this realm of research, Demetri says. 

Dr. Demetri on the Evolving Field of Sarcoma

George D. Demetri, MD, Director, Center for Sarcoma and Bone Oncology Senior Vice President for Experimental Therapeutics, Professor of Medicine, Harvard Medical School, Dana Farber Cancer Center, discusses a phase III study of trabectedin verus dacarbazine for the treatment of patients with advanced liposarcoma (LPS) or leiomyosarcoma (LMS).

Trabectedin is a multifunctional drug derived from a sea squirt, which is now manufactured synthetically. The sarcoma community is particularly interested in this drug because it has been showed to produce extremely good response and durable disease stability, sometimes lasting four to five years, said Demetri.

However, there is no predictive biomarker to determine which patients will benefit from this drug. The aim of the study was to determine which patients responded more favorably to trabectedin versus the standard of care dacarbazine.

The study is ongoing, however an interim analysis presented at ASCO 2015, showed that trabectedin had a significant benefit over dacarbazine in terms of disease control and progression-free survival.

Dr. George Demetri on Trabectedin for Sarcomas

George Demetri, MD, director of the Ludwig Center at Dana-Farber Cancer Institute and Sarcoma Center at Harvard Medical School in Boston, Massachusetts, discusses the oral multikinase inhibitor regorafenib that is being investigated for patients with gastrointestinal stromal tumors (GISTs).

GISTs are driven primarily by mutations in the KIT kinase pathway, Demetri explains. Overtime, 90% of patients receiving imatinib (Gleevec) and sunitinib (Sutent) for their GIST will develop resistance. Following progression, the unique shape of the regorafenib molecule allows it to bind to targets that have developed resistance to sunitinib and imatinib, according to Demetri.

Overall, regorafenib has a very different profile than the other agents used to treat GIST. Its ability to specifically inhibit fibroblast growth factor receptors (FGFR) is still being investigated as a possible route for overcoming resistance. In total, regorafenib inhibits VEGFR1-3, TIE2, PDGFR, FGFR, KIT and RET.

For the treating oncologist, Demetri notes that the unique activity of regorafenib, as demonstrated in the phase III GRID trial, justifies the agent for patients with GIST who have no other therapeutic options. In the trial, the risk of disease progression was reduced by 73% when compared to placebo for patients who were resistant to imatinib or sunitinib.

Dr. George Demetri, from the Dana-Farber Cancer Institute, Describes the Mechanism of Action of Regorafenib in Gastrointestinal Stromal Tumors.

Dr. Demetri Describes the MOA of Regorafenib in GIST

George Demetri, MD, Director of the Ludwig Center and Sarcoma Center at Dana-Farber Cancer Institute and Harvard Medical School in Boston, explains the side effects associated with the oral multikinase inhibitor regorafenib, which targets the 

 mutations while also blocking angiogenesis through dual VEGF receptor inhibition.

The side effects of regorafenib were assessed in a randomized phase III trial of 199 patients with gastrointestinal stromal tumors (GIST) that had developed a resistance to imatinib and sunitinib. Demetri notes that the side effects exhibited by regorafenib were similar to those seen with other multikinase inhibitors, especially those that prevent angiogenesis, such as the agent sunitinib, which is also used to treat GIST.

The two leading side effects associated with regorafenib were hand-foot syndrome and hypertension, which is a common adverse reaction for VEGF blocking agents. In general, Demetri notes that the side effects of regorafenib were similar to those seen with sunitinib and could be managed in the same fashion.

Dr. George Demetri, from Dana-Farber Cancer Institute, Explains the Side Effects Associated With Regorafenib.

George D. Demetri, MD

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