BLU-667 Continues to Show Durable Responses in RET-Altered Thyroid Cancers

Matthew H. Taylor, MD

Matthew H. Taylor, MD

The RET inhibitor BLU-667 induced durable responses in patients with advanced,RET-altered medullary thyroid cancer (MTC) and papillary thyroid cancer (PTC), according to updated results of the ARROW trial focused on the patients with thyroid cancer that were presented at the 2019 ASCO Annual Meeting.

“BLU-667 demonstrates broad and durable antitumor activity in patients with advanced,RET-altered MTC and PTC,” the study authors, led by Matthew H. Taylor, MD, wrote in their poster. “Responses [were] observed regardless of treatment history orRETmutation genotype.”

BLU-667 received a breakthrough therapy designation from the FDA based on responses seen in the phase I trial.

The ARROW study (NCT03037385) is an ongoing phase I dose-escalation/expansion study looking at the safety and preliminary activity of BLU-667 in patients with advanced medullary thyroid cancer and otherRET-altered solid tumors. Part 1 of the trial enrolled 62 patients to receive varying doses of the selective RET inhibitor from 30 mg to 600 mg, once daily or twice daily. The recommended dose was determined to be 400 mg daily.

Part 2 is continuing to enroll patients in cohorts by tumor type and prior treatment, including patients withRETfusion—positive non–small cell lung cancer and those who have received a prior selective RET inhibitor. Patients with unresectable, advanced solid tumors harboring aRETalteration and no other driver mutations are eligible for the trial. The primary endpoints of the dose-expansion portion of the trial are overall response rate (ORR) and safety.

Sixty-four patients withRET-mutated MTC were treated with 400 mg of BLU-667 daily; 43 of these patients had received prior treatment with cabozantinib (Cabometyx) and/or vandetanib (Caprelsa). The median age across all 64 patients was 59 years (range, 19-81), and 66% each were male and had an ECOG performance status of 1 or 2. Patients had received a median of 1 prior systemic treatment regimen (range, 0-10). The most commonRETmutation was M918T in 56%.

Response was evaluable in 32 patients who had been enrolled by November 14, 2018, and the ORR was 56% (95% CI, 38%-74%), consisting of 1 complete response and 17 partial responses. An additional 13 patients achieved stable disease for a disease-control rate (DCR) of 97% (95% CI, 84%-100%).

Sixteen of these patients had received treatment with a prior RET inhibitor, cabozantinib or vandetanib, and the ORR was 63% (95% CI, 35%-85%) among these patients, and the DCR was 94% (95% CI, 70%-100%).

All 18 patients who had a tumor response to treatment remain on BLU-667 as of the data cutoff date. The median duration of response has not yet been reached.

The most common (≥25%) treatment-emergent adverse events (AEs) in patients withRET-mutated MTC were hypertension (any grade, 41%; grade ≥3, 23%), constipation (any grade, 33%; grade ≥3, 2%), and neutropenia (any grade, 27%; grade ≥3, 11%). Frequent treatment-related AEs included hypertension (any grade, 30%; grade ≥3, 16%), neutropenia (any grade, 23%; grade ≥3, 11%), constipation (any grade, 19%; grade ≥3, 2%), and leukopenia (any grade, 17%; grade ≥3, 0%).

The investigators noted that treatment-related toxicity was generally low-grade and reversible, and none of these patients in the MTC cohort discontinued BLU-667 due to treatment-related toxicity. In fact, the rate of discontinuation due to treatment-related AEs was 4% across the study.

Significant reductions in calcitonin and carcinoembryonic antigen levels were also noted from baseline to cycle 2 of treatment.

Nine patients withRETfusion—positive PTC were enrolled, although only 5 of these patients have received treatment for at least 1 year. The median age in the patients with PTC was 66 years (range, 23-70), and 56% each were male and had an ECOG performance status of 1 or 2. The median number of prior systemic treatments was 2 (range, 0-8), which included radioactive iodine in 89%. TheRETfusion partner was CCDC6 or NCOA4 in 4 patients each, and SNRNP70 in 1.

The ORR was 83% in 6 evaluable patients withRETfusion—positive PTC, although responses are still pending for 2 patients, and 8 of 9 patients are continuing to receive treatment.

The safety profile in the PTC cohort was similar to that of the MTC cohort and no patients with PTC discontinued BLU-667 due to treatment-related toxicity.

Reference:

Taylor MH, Gainor JF, Hu MI-N, et al. Activity and tolerability of BLU-667, a highly potent and selective RET inhibitor, in patients with advanced RET-altered thyroid cancers.J Clin Oncol.2019;37(suppl 15; abstr 6018). doi: 10.1200/JCO.2019.37.15_suppl.6018.