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Cobimetinib in Pediatric and Young Adult Patients with Relapsed or Refractory Solid Tumors (iMATRIX-cobi): A
Tanya Trippett1, Helen Toledano2, Quentin Campbell Hewson3
1Department of Pediatrics, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA. trippet1@MSKCC.ORG.
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 (Cmax, AUC0-24) 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.
Insights
Cobimetinib showed clinical activity in pediatric patients with MAPK-altered solid tumors, particularly low-grade glioma. Further combination therapies may be needed to improve response rates in this young population.
Area of Science:
- Oncology
- Pharmacology
- Genetics
Background:
- The MAPK pathway is a key target in adult and pediatric tumors.
- MEK1 inhibition is a strategy to control MAPK-dependent tumor growth.
Purpose of the Study:
- To assess the safety, pharmacokinetics, and anti-tumor activity of cobimetinib in pediatric and young adult patients with relapsed/refractory solid tumors.
- To establish a recommended Phase II dose (RP2D) for cobimetinib in this population.
Main Methods:
- A multicenter Phase I/II study (iMATRIX-cobi) enrolled patients aged 6 months to <30 years with MAPK pathway-involved solid tumors.
- Patients received cobimetinib via tablet or suspension, with dose escalation using a rolling 6 design.
- Primary endpoint was safety; secondary endpoints included pharmacokinetics and anti-tumor activity.
Main Results:
- 56 patients were enrolled; most common diagnoses were low-grade glioma (LGG) and plexiform neurofibroma.
- A pediatric RP2D of 0.8 mg/kg (tablet) and 1.0 mg/kg (suspension) was established after dose-limiting toxicities were observed.
- Overall response rate was 5.4%, with partial responses seen in LGG patients. Pediatric exposure was approximately 50% lower than in adults.
Conclusions:
- Cobimetinib demonstrated a similar safety profile in pediatric patients compared to adults.
- Clinical activity was observed in pediatric LGG patients with MAPK pathway activation.
- Combination regimens of cobimetinib may be necessary to enhance response rates in pediatric solid tumors.
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