Brigatinib monotherapy in children with R/R ALK+ ALCL, IMT, or other solid tumors: Results from the BrigaPED (ITCC-098) phase 1 study.

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10017 Background: Brigatinib is a potent ALK inhibitor (ALKi), with good CNS penetration and durable efficacy in adults with ALK-positive ( ALK+) non-small cell lung cancer at 180 mg/day after a 7-day lead-in at 90 mg/day. This report presents the results of a pediatric phase 1 study (NCT04925609) in patients (pts) with ALK+ malignancies. The study is sponsored by the Princess Máxima Center and supported by Takeda Pharmaceuticals International Co. Methods: This multicenter, non-randomized, open-label phase 1 study enrolled pediatric pts aged ≥ 1 to < 18 years, with ALK+ newly diagnosed unresectable/metastatic or relapsed/refractory (R/R) IMT, R/R ALCL, or other solid tumors. ALK+ ALCL pts who were MRD positive after one course of frontline chemotherapy were considered refractory disease. A proven ALK gene aberration was required, except in ALCL, where ALK+ by immunohistochemistry was sufficient. Pts had to be able to swallow tablets and to weigh more than 10 kg at trial entry. Brigatinib was administered as tablets once daily in 28-day cycles, and was dose-escalated according to the rolling-six design to a maximum of 3 dose levels (DL). Dose limiting toxicities (DLTs) were evaluated during 35 days (1st cycle preceded by a 7-day lead-in phase), to determine the RP2D. Pts were assessed for safety, pharmacokinetics (PK) and efficacy. Results: Ten pts were enrolled (5 centers, 2 countries) over 12 months, including 9 ALCL, and 1 sarcoma NOS, with an ALKfusion. Median age was 9 years (range: 6-17) and 2 pts were pretreated with another ALKi. No pts less than 6 years were included due to the lack of age-appropriate formulation (AAF). At database cut-off, a median of 13 cycles (range 4-17) were administered. No DLTs were observed on DL1 (n = 4), and only 1 on DL2 (N = 6, grade (G)3 neutropenia > 7 days). Common treatment related adverse events (AE) were (n any G; n ≥G3): abdominal pain (6;0), CPK increase (7;1), nausea/vomiting (6;0), AST/ALT elevation (4;0). Reported AEs of special interest included ophthalmological events (3;0) and weight gain (2;1), no brigatinib related pulmonary toxicity or endocrine AEs were observed. PK exposure at DL2 was equivalent to that reported in adults at the approved dose. The sarcoma patient had progressive disease after 12 cycles. All 9 ALCL patients are still on therapy with an ongoing response. Conclusions: The RP2D of brigatinib was established at DL2, corresponding to 150 mg (18-40 kg), or 240 mg ( > 40 kg) once daily. In general, the drug was well tolerated, with no instances of patients discontinuing dosing due to safety concerns. Brigatinib monotherapy demonstrated promising preliminary signs of efficacy in pediatric ALCL, although follow-up is still limited. The phase 2 part of this study has recently opened for accrual, and an AAF will soon be available for smaller children to define the RP2D in this population. Clinical trial information: NCT04925609 .