Rare Tumors in Kids May Respond to Tazemetostat

In a phase I trial of the investigational EZH2 inhibitor tazemetostat (Epizyme), children with INI1-deficient tumors—relapsed or refractory malignant rhabdoid tumors, atypical teratoid rhabdoid tumors (ATRT), epithelioid sarcomas, and poorly differentiated chordomas, for example—responded well to treatment, with some experiencing durable responses. Researchers reported their findings at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics, held October 26–30 in Philadelphia, PA.

INI1, also known as SMARCB1, is a subunit of the SWI/SNF chromatin remodeling complex, which normally keeps the histone methyltransferase complex PRC2 in check. Loss of INI1 impairs SWI/SNF's function, driving aberrant PRC2 activity and causing cancer cells to become dependent on PRC2′s catalytic subunit, EZH2. Tazemetostat, which targets EZH2, has been shown to induce tumor regression in preclinical models and in some adults with INI1-negative tumors.

“Children with these tumors have a poor prognosis despite conventional treatment regimens, and, because of their rarity, there are no uniform treatment approaches,” said Susan Chi, MD, of the Department of Pediatric Neuro-oncology at Dana-Farber Cancer Institute in Boston, MA, who presented the findings.

That prompted Chi and her colleagues to launch the first-ever clinical trial evaluating EZH2 inhibitors in children. They enrolled 46 patients ranging in age from 6 months to 21 years, with a median age of 3 years, with relapsed or refractory INI1-negative tumors. Patients received one of seven doses of the drug, which ranged from 240 mg/m² to 1,200 mg/m² twice a day.

Tumors completely regressed in three patients—one with poorly differentiated chordoma, one with epithelioid sarcoma, and one with ATRT, Chi reported. A second patient with poorly differentiated chordoma experienced a partial response. All four responders received doses of at least 520 mg/m² of tazemetostat and have continued on the study; one remains in remission after more than a year.

Adverse events (AE) were consistent with those previously reported in adults, Chi said, and were mostly mild to moderate; vomiting, fever, and cough were the most common. Interestingly, fewer grade 3 and grade 4 side effects occurred in patients who received at least 520 mg/m² of tazemetostat than in patients who received lower doses. However, “we should recognize the limitation of patient numbers [because] the frequency of such AEs only in the lower doses may not be statistically significant compared to those at higher doses,” she noted.

“Overall, it was a very well-tolerated medication,” Chi added.

Researchers selected a dose of 1,200 mg/m² for the next phase of the trial “based on a variety of parameters including an observed plateauing of pharmacokinetics, pharmacodynamics, and signal of clinical activity already seen,” Chi explained. In addition, they hope that the high dose will result in more of the drug reaching brain and central nervous system (CNS) tumors, but “whether this will result in broad activity in primary CNS tumors or not is still to be determined,” she said.

Researchers are now enrolling patients into four dose-expansion cohorts, three of which are disease specific. A fourth will test a tablet form of the drug in all types of INI1-deficient tumors instead of the liquid formulation required for young children. –Suzanne Rose