Side Effects of Targeted Therapies: From MEK Inhibitor Rash to Tovorafenib Growth Concerns

In this segment, Dr. Margol, Dr. Abdelbaki, Dr. Chintagumpala, and Dr. Chi review the side effect profiles of targeted agents used in pediatric low-grade glioma (PLGG) and discuss practical considerations for tovorafenib use.

Targeted agent side effects can sometimes be worse than those of conventional chemotherapy, a point not always appreciated by families or providers. For MEK inhibitors (selumetinib, trametinib, binimetinib, mirdemetinib), rash is the most common and sometimes treatment-limiting toxicity, particularly burdensome for adolescent and young adult patients who may require clinic visits as frequent as those for chemotherapy. Other MEK inhibitor effects include skin dryness, hair color changes, potential cardiac dysfunction requiring echocardiographic monitoring, weight gain (notably with binimetinib), generalized edema, muscle weakness, and creatine phosphokinase (CPK) elevation. For tovorafenib, key concerns include hyperphosphatemia, hair depigmentation, fatigue (especially in teenagers), and decreased growth velocity.

Growth velocity suppression with tovorafenib occurs in most patients. While catch-up growth has been observed and no premature growth plate closure has been reported, long-term data are lacking. Timing matters: Prepubertal patients (ages 13–14) have limited remaining growth time and may not recover, whereas younger children have more opportunity for catch-up. This concern influences when tovorafenib is introduced, though it remains a valuable option for progressive disease after first-line therapy. In multiply recurrent cases, tovorafenib can serve as a bridge therapy—leveraging its rapid onset of response to stabilize acute vision loss while a slower-acting MEK inhibitor or chemotherapy takes effect, then discontinuing it to minimize growth impact. Regarding intratumoral hemorrhage, the rate observed in the tovorafenib study is difficult to distinguish from the natural history of PLGG and has not precluded its use.

In the next episode, "Recurrent Progressive PLGG: Sequencing Targeted Therapies, Retreatment, and the Role of Radiation," the panel discusses treatment decision-making in the recurrent or progressive setting, including the strategic role of retreatment and radiation therapy.