Pralsetinib is an investigational, potent, highly selective RET kinase inhibitor that acts by targeting oncogenic RET alterations. The global ARROW study is designed to evaluate pralsetinib in patients with medullary thyroid cancer, RET-altered non–small-cell lung cancer (NSCLC), and other RET-altered solid tumors. The registrational data set from the ARROW study for patients who have RET fusion–positive NSCLC with and without prior treatment was reported at the 2020 ASCO Annual Meeting.
In the ongoing ARROW trial of pralsetinib, patients with advanced RET-altered solid tumors are treated with a phase 1 dose escalation (30-600 mg once or twice daily) followed by a phase 2 expansion (400 mg once daily). The primary outcome measures are overall response rate (ORR) and safety. The investigators report efficacy analyses for response-evaluable patients with RET fusion–positive NSCLC who initiated treatment with pralsetinib 400 mg once daily by July 11, 2019, as well as safety for all patients, regardless of diagnosis, who were treated with pralsetinib 400 mg once daily.
As of November 18, 2019, a total of 354 patients with advanced solid tumors had received pralsetinib at a starting dose of 400 mg once daily. Median follow-up was 8.8 months. Of 116 patients with metastatic RET fusion–positive NSCLC, 72% had fusions involving KIF5B, 16% involving CCDC6, and 12% with other fusions of unknown type. A total of 80 patients had received prior platinum treatment, 10 had received nonplatinum treatment, and 26 patients had received no prior systemic treatment.
The ORR was similar regardless of RET fusion partner, prior therapies, or central nervous system involvement. Overall, the ORR was 65% (95% confidence interval [CI], 55%-73%). The ORR for patients with prior platinum treatment was 61% (95% CI, 50%-72%) and 73% (95% CI, 52%-88%) for patients with no prior systemic treatment. The overall disease control rate was 93% (95% CI, 87%-97%). The disease control rate was 95% (95% CI, 88%-99%) for patients with prior platinum-based chemotherapy treatment, and 88% (95% CI, 70%-98%) for patients without prior systemic treatment. Tumor size reduction was observed in 95% of patients with prior platinum treatment, 100% of patients without prior systemic treatment, and in 96% of patients overall.
There were 7 (6%) complete responses overall, with 4 (5%) in patients with prior platinum treatment and 3 (12%) in patients with no prior systemic treatment. The median time to response overall was 1.8 months. The median duration of response was not reached (95% CI, 11.3 months-not reached).
Among the safety population of 354 patients of all tumor types, most treatment-related adverse events were grade 1 or 2. These included increased aspartate aminotransferase (31%), anemia (22%), increased alanine aminotransferase (21%), constipation (21%), hypertension (20%), and neutropenia (19%). The most common grade ≥3 adverse events were hypertension and neutropenia, with each occurring in 10% of patients. Overall, 4% of patients in the safety population discontinued treatment due to treatment-related adverse events.
These updated, registrational, centrally reviewed data from the ongoing ARROW study demonstrate that pralsetinib has rapid, potent, and durable clinical activity in patients with advanced RET fusion–positive NSCLC. This activity was present regardless of RET fusion genotype or history of prior therapies, and once daily dosing of pralsetinib was well-tolerated overall. Study investigators conclude that these data suggest that pralsetinib has the potential to change the standard of care for patients with RET fusion–positive NSCLC.
Source: 2020 ASCO Annual Meeting. Abstract 9515.