Next-Generation ROS1/TRK/ALK Inhibitor Under Study in Neuroblastoma
Posted: Thursday, January 6, 2022
Andrew L. Kung, MD, PhD, of Memorial Sloan Kettering Cancer Center, New York, and colleagues evaluated the preclinical activity of repotrectinib, a next-generation multikinase inhibitor that targets ALK, TRK, JAK2/STAT, and Src/FAK in patients with relapsed or refractory neuroblastoma. Published in Molecular Cancer Therapeutics, the results of this study showed the novel agent demonstrates antitumor activity and may prove to be an effective treatment for this type of peripheral nervous system cancer when combined with chemotherapy.
Neuroblastoma cell lines were obtained from the American Type Culture Collection and German Collection of Microorganisms and Cell Cultures. Dose-response studies of repotrectinib were performed using serial dilutions ranging from 100 µmol/L to 0.001 µmol/L, and 1.25-fold dilutions of repotrectinib or the ALK inhibitor ensartinib, irinotecan, and temozolomide were used to evaluate combination therapy. Patient-derived xenograft mouse models were used to assess combination therapy in vivo.
According to the investigators, there was a significant difference in tumor volume change between repotrectinib (14%) and vehicle (149%) treatment (P = .005) groups, with the ensartinib group (73%) also demonstrating improvement over the vehicle group. Additionally, ALK wild-type models treated with repotrectinib showed greater relative tumor volume change compared with the vehicle groups (P = .041); in addition, repotrectinib yielded a significant event-free survival advantage compared with the vehicle or ensartinib arms among the entire cohort (P < .05).
All treatments appeared to be well tolerated, with no signs of systemic toxicity or weight loss, the authors reported. Repotrectinib demonstrated comparable cytotoxic activity across all cell lines, regardless of ALK mutational status. Notably, targeted inhibition in combination with chemotherapy demonstrated a robust cytotoxic effect in ALK-mutated and two ALK wild-type cell lines. Repotrectinib monotherapy also showed notable antitumor activity, and when combined with chemotherapy, it displayed increased antiproliferative activity across multiple cell lines. Of note, repotrectinib in combination with chemotherapy was superior to chemotherapy alone in both ALK-mutant and wild-type patient-derived xenograft models (P = .025).
Disclosure: For full disclosures of the study authors, visit mct.aacrjournals.org.