Cobimetinib in Pediatric and Young Adult Patients with Relapsed or Refractory Solid Tumors (iMATRIX-cobi): A Multicenter, Phase I/II Study

BACKGROUND: The MAPK pathway is an emerging target across a number of adult and pediatric tumors. Targeting the downstream effector of MAPK, MEK1, is a proposed strategy to control the growth of MAPK-dependent tumors. OBJECTIVE: iMATRIX-cobi assessed the safety, pharmacokinetics, and anti-tumor activity of cobimetinib, a highly selective MEK inhibitor, in children and young adults with relapsed/refractory solid tumors. PATIENTS AND METHODS: This multicenter Phase I/II study enrolled patients aged 6 months to < 30 years with solid tumors with known/expected MAPK pathway involvement. Patients received cobimetinib tablet or suspension formulation on Days 1–21 of a 28-day cycle. Dose escalation followed a rolling 6 design. The primary endpoint was safety; secondary endpoints were pharmacokinetics and anti-tumor activity. RESULTS: Of 56 enrolled patients (median age 9 years [range 3–29]), 18 received cobimetinib tablets and 38 cobimetinib suspension. Most common diagnoses were low-grade glioma (LGG; n = 32, including n = 12 in the expansion cohort) and plexiform neurofibroma within neurofibromatosis type 1 (n = 12). Six patients (11 %) experienced dose-limiting toxicities (including five ocular toxicity events), which established a pediatric recommended Phase II dose (RP2D) of 0.8 mg/kg tablet and 1.0 mg/kg suspension. Most frequently reported treatment-related adverse events were gastrointestinal and skin disorders. Steady state mean exposure (C(max), AUC(0–24)) of cobimetinib at the RP2D (1.0 mg/kg suspension) was ~ 50 % lower than in adults receiving the approved 60 mg/day dose. Overall response rate was 5.4 % (3/56; all partial responses in patients with LGG). CONCLUSIONS: The safety profile of cobimetinib in pediatrics was similar to that reported in adults. Clinical activity was observed in LGG patients with known/suspected MAPK pathway activation. Cobimetinib combination regimens may be required to improve response rates in this pediatric population. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT02639546, registered December 24, 2015. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s11523-022-00888-9.