Pralsetinib Active in RET-Mutant Advanced Medullary Thyroid Cancer

Potent and durable clinical activity was shown with pralsetinib (Gavreto) as treatment of patients with RET-mutant advanced medullary thyroid cancer (MTC), regardless of the line of therapy, according to results from the phase 1/2 ARROW clinical trial (NCT03037385) presented during the European Society of Medical Oncology (ESMO) Virtual Congress 2020.¹

In the presentation given by Mimi I. Hu, MD, it was explained that FDA-approved agents in the field—such as cabozantinib (Cabometyx) and vandetanib (Calpresa)—often require many dose reductions and lead to treatment discontinuations as a result of adverse effects (AEs). Thus, pralsetinib may serve an unmet medical need in RET-mutant MTC with limited toxicity.

Pralsetinib is a highly potent and selective inhibitor of wild-type RET and RET oncogenic alteration, according to Hu. Alterations that pralsetinib inhibits include the V804M/L gatekeeper mutations.

“For patients with RET-mutant medullary thyroid cancer, there is an important need for targeted therapies like pralsetinib that are highly active across RET genotypes, including gatekeeper resistance mutations,” Hu, professor of the Department of Endocrine Neoplasia and Hormonal Disorders in the Division of Internal Medicine at The University of Texas MD Anderson Cancer Center in Houston, said in a statement to the press.² “The reported data highlight the robust clinical activity and safety of [pralsetinib], with most patients remaining on treatment for prolonged periods of time. These results are a promising advancement for RET-mutant medullary thyroid cancer across both systemic treatment-naïve and previously treated patients.”

Activity observed with pralsetinib in 53 previously treated patients in the ARROW study included a high objective response rate (ORR) of 60% (95% CI, 46%-74%). Responses included complete responses (CRs) in 2% of patients and partial responses (PRs) in 58%. It was noted that 36% of patients treated pralsetinib had stable disease and 4% had progressive disease. The disease control rate in these patients was 96% (95% CI, 87%-100%). Among treatment-naïve patients who were not eligible to receive standard therapies, the ORR was 74% and the DCR was 100%.

The median duration of response (DOR) was not reached (NR) in patients with prior cabozantinib or vandentanib (95% CI, NR-NR). The median progression-free survival (PFS) was also NR (95% CI, NR-NR). Hu noted, however, that 75% of patients in the previously treated population who were evaluable for efficacy remained on treatment at the time of data cutoff, while 94% of patients with responses continued to receive pralsetinib. Only 2 patients who experienced responses in this group had progressive disease.

In the treatment-naïve population, 82% of efficacy-evaluable patients remained on treatment at data cutoff, with 93% of responders still on therapy. In addition, 2 patients in the treatment-naïve group who initially responded to treatment eventually developed progressive disease.

“I was very pleased with these kinds of responses. Our experience with prior multikinase le inhibitors were such that we saw responses, but they weren’t as dramatic as with the RET inhibitors,” Hu stated. “Honestly, about 6 years ago, I didn’t believe that RET [inhibition] was going to be enough for the disease and thought that a RET inhibitor alone may not be fully effective.”

The positive responses observed with pralsetinib in patients with RET-mutant MTC were regardless of RET mutation genotype. Notably, in a subset of patients with a RET V804X gatekeeper mutation, 83% responded to pralsetinib.

In terms of safety, the 400 mg once daily dose of pralsetinib was well-tolerated in patients. The median dose intensity of the drug was 92% (range, 18%-100%). The majority of treatment-related AEs were grade 1 and 2 in severity and were reversible. The most common all-grade treatment-related AEs were aspartate aminotransferase increase (34%), anemia (24%), alanine aminotransferase increase (23%), hypertension (22%), and constipation (23%). The most frequent grade 3 or greater treatment-related AEs were hypertension (11%), neutropenia (10%), anemia (8%), and neutrophil count decreased (6%). Only 4% of patients discontinued pralsetinib due to treatment-related AEs.

In the ARROW trial, eligible patients included those with advanced solid tumors, RET-altered disease per local testing, no other driver mutations, an ECOG performance status of 0 to 1, and those who previously received standard therapy or who were not candidates for standard therapy. The key study end points were ORR, DOR, and safety.

Four cohorts were included in ARROW of 67 patients with RET-mutant MTC with prior cabozantinib and/or vandetanib, 42 patients with RET-mutant MTC who did not have prior systemic treatment, 10 patients with RET-mutant MTC who had prior systemic treatment other than cabozantinib and vandetanib, and 319 patients with other RET-altered tumors.

In the RET-mutant MTC population at baseline, the median age of patients enrolled to receive pralsetinib was 59 years (range, 19-83). Sixty-eight percent of the study population was male. A higher percentage (60%) of patients had an ECOG performance status of 1 or 2 at baseline compared with a status of 0, which was true for 40%. Ten percent of patients had a history of central nervous system/brain metastases. In terms of RET genotype, 61% of patients had RETM918T–mutant tumors, 29% had cysteine-rich domain, 3% had mutations in RET V804M/L, and the remaining 7% had other RET alterations. Baseline demographics were comparable between the previously treated and treatment-naïve populations.

ARROW is an international, mutlicenter trial that is ongoing. The study is being conducted across 84 sites in 11 countries. Based on data from ARROW, the FDA is currently considering a New Drug Application (NDA) for pralsetinib as treatment for patients with advanced or metastatic RET-mutant MTC, as well as for patients with RET fusion–positive thyroid cancer. The NDA was granted Priority Review by the FDA in early September.^1,3

References:

1. Hu M, Subbiah V, Wirth L, et al. Results from the registrational phase 1/2 ARROW trial of pralsetinib (BLU-667) in patients (pts) with advanced RET mutation-positive medullary thyroid cancer (RET+ MTC). Presented at 2020 Virtual ESMO Congress; September 19-October 21, 2020. Abstract 1913O.
2. Blueprint Medicines reports ARROW trial data at ESMO Virtual Congress 2020 demonstrating durable clinical benefits of Gavreto™ (pralsetinib) in patients with advanced ret-mutant medullary thyroid cancer. News release. September 20, 2020. Accessed September 20, 2020. https://bit.ly/3kDgGLz
3. Blueprint Medicines announces the achievement of key portfolio milestones. News release. Blueprint Medicines Corporation. April 1, 2020. Accessed September 20, 2020. https://bit.ly/2R3cW9R​