Fusions involving the RET gene are oncogenic drivers in many tumor types, including up to 20% of papillary thyroid cancers. Pralsetinib is an investigational, highly selective inhibitor of oncogenic RET alterations. The ongoing phase 1/2 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 tumors. Pralsetinib has demonstrated antitumor activity in patients with RET fusion–positive NSCLC, with an overall response rate (ORR) among response-evaluable patients of 73% (19/26) in those who were treatment-naïve and 61% (49/80; 2 pending confirmation) in those previously treated with platinum chemotherapy. Treatment with pralsetinib has been demonstrated to be well-tolerated. An update on the clinical activity of pralsetinib in other RET fusion–positive solid tumor types was presented at the 2020 ASCO Annual Meeting.
In the global ARROW study, 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). ORR and safety are the primary objectives. As of November 18, 2019, a total of 29 patients with metastatic solid tumor types with a RET fusion received pralsetinib. Of these patients, 16 had papillary thyroid cancer, 1 had undifferentiated thyroid cancer, 3 had pancreatic cancer, 3 had colon cancer, and 6 had other cancers. The authors present efficacy data for response-evaluable patients enrolled by July 11, 2019.
In patients with RET fusion–positive thyroid cancer, the ORR by investigator assessment was 75% (9/12). The median duration of response (DOR) was 14.5 months (range, 3.7+ to 16.8 months) with 67% of responding patients continuing treatment. Two patients with stable disease were continuing treatment at 11.5+ and 19.3+ months. In other RET fusion–positive cancers, the ORR was 60% (3/5). Partial responses were reported in 2/2 patients with pancreatic cancer, with a DOR of 5.5 and 7.4+ months, and in 1 patient with intrahepatic bile duct carcinoma, with a DOR of 7.5 months. Two patients with colon cancer had stable disease for 7.3 and 9.3 months. Investigators observed responses across multiple fusion genotypes.
Pralsetinib was well-tolerated overall. Of the 354 patients in the safety population consisting of all patients treated with 400 mg once daily, regardless of diagnosis, only 4% discontinued treatment due to treatment-related adverse events. Most adverse events were grade 1 or 2 in severity, and included increased aspartate aminotransferase (31%), anemia (22%), increased alanine aminotransferase (21%), constipation (21%), and hypertension (20%).
The study investigators concluded that pralsetinib demonstrated broad and durable antitumor activity across multiple advanced solid tumor types, regardless of RET fusion genotype, and was well-tolerated. The ongoing ARROW study is still enrolling patients in this cohort.
Source: 2020 ASCO Annual Meeting. Abstract 109.
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