Early phase clinical trials conducted by researchers from The University of Texas MD Anderson Cancer Center show promising results for patients with RET fusion-positive cancers, high-grade (HGG) and low-grade glioma (LGG) and ovarian cancer.
The results, presented today at the virtual American Association for Cancer Research (AACR) Annual Meeting 2021, showcase the researchers’ ongoing efforts to advance clinical studies and expand potential indications of approved drugs to develop a platform for more effective treatments and to improve patient outcomes.
FDA-approved selpercatinib shows clinical benefits for RET fusion-positive cancers beyond lung and thyroid cancers (Abstract CT011)
Clinical trial results of RET kinase inhibitor selpercatinib show that the targeted therapy was effective in preventing or inhibiting the growth of tumors in RET fusion-positive cancers other than lung and thyroid cancers. The results, derived from a cohort of patients enrolled in the phase 1/2 LIBRETTO-001 trial, were presented by Vivek Subbiah, M.D., associate professor of Investigational Cancer Therapeutics.
“Selpercatinib demonstrates promising activity across a variety of non-lung and non-thyroid RET fusion-positive advanced solid tumors, including treatment-refractory GI malignancies,” Subbiah said. “Although RET fusions are rare, this undoubtedly has conferred clinical benefit and the gift of time to these patients.”
The safety profile of this cohort is consistent with the known profile of selpercatinib in the overall LIBRETTO-001 population. The LIBRETTO-001 trial, which spans 16 countries and 89 sites, continues to enroll patients with RET-altered non-lung cancer.
Combining dabrafenib and trametinib to treat BRAF V600E-mutant high-grade (HGG) and low-grade glioma (LGG) shows significant antitumor activity (Abstract CT025)
In a nonrandomized, open-label phase 2 study, MD Anderson researchers showed that the combination of BRAF inhibitor dabrafenib and MEK inhibitor trametinib had promising efficacy in patients with BRAF V600 mutation-positive HGG and LGG.
The FDA approved a combination therapy of BRAF inhibitor dabrafenib and MEK inhibitor trametinib, which blocks proteins that facilitate cancer cell growth, to treat patients with BRAF V600-positive melanoma, non-small cell lung carcinoma and anaplastic thyroid cancer.
“Glioblastoma is a very difficult-to-treat tumor and has historically shown resistance to therapies, and this is the first time that a targeted therapy has shown significant activity in these challenging tumors,” said Subbiah, who presented these findings.
The HGG arm of the trial enrolled 45 patients previously treated with radiotherapy, surgery or chemotherapy. A majority of patients had glioblastoma, while the rest had anaplastic pleomorphic xanthoastrocytoma and anaplastic astrocytoma.
After undergoing the combination therapy, patients showed a 33% objective response rate. The tumors continued to respond to treatment without cancer growth or spread for 36.9 months.
While 13 patients were enrolled in the LGG cohort, eight patients — who were previously treated with surgery, radiotherapy and chemotherapy — were evaluated in the study and achieved an objective response rate of 69%. The median duration of response, median progression-free survival and median overall survival rates were not reached.
Among both cohorts, 54 patients (93%) experienced a common adverse event — including fatigue, headache, nausea and fever — and 31 patients (53%) experienced a Grade 3 or greater adverse event — such as fatigue, decreased neutrophil count, headache and neutropenia. No new safety signals were detected.
Therapeutics Discovery researchers identify key biomarker for metabolic inhibitor (Abstract 87)
Researchers from MD Anderson’s Therapeutics Discovery division previously reported the discovery and development of IACS-6274, a novel small-molecule inhibitor targeting the metabolic enzyme glutaminase (GLS1). Through a patient-driven translational biology effort, the researchers now have identified and validated asparagine synthetase (ASNS) as a candidate biomarker to predict those most likely to benefit from the therapy.
The new findings were shared in a minisymposium presentation by Nakia D. Spencer, institute associate scientist IV with the Translational Research to Advance Therapeutics and Innovation in Oncology (TRACTION) platform and one of the GLS1 project leads.
The development of IACS-6274, previously known as IPN60090, was initiated and advanced by a team of scientists in the Institute for Applied Cancer Science (IACS) and TRACTION platforms, both engines within Therapeutics Discovery. The drug is now under investigation in a Phase I trial for advanced solid tumors.
“Ovarian cancer remains an area of unmet medical need for our patients,” Spencer said. “Utilizing team science to drive patient-focused research, we discovered that ovarian tumors lacking ASNS respond to IACS-6274 treatment, pointing us toward a significant number of patients who may benefit from this therapy.”
“Advancing treatments that provide the greatest benefits to patients requires a strong translational and drug discovery package that complements the clinical efforts,” Spencer said. “Applying what we’ve learned from the clinical study, we continue to develop multiple biomarker-driven patient stratification strategies to identify those most likely to benefit from IACS-6274.”
Therapeutics Discovery researchers will share additional updates on IACS-6274 development in poster sessions, including the identification of rational combination strategies for GLS1 inhibitors and the effects of IACS-6274 on the antitumor immune response.