FDA Grants Priority Review to Pralsetinib for Metastatic RET+ Thyroid Cancers

The FDA has granted pralsetinib (Gavreto) a priority review for the treatment of patients with advanced or metastatic RET-mutant medullary thyroid cancer and RET fusion–positive thyroid cancer, according to an announcement from Genentech, the drug developer.¹

The new drug application (NDA) was accepted for review under the FDA’s Real-Time Oncology Review pilot program, which seeks to provide a more efficient review process to make safe and effective therapies available to patients as rapidly as possible.

Under the Prescription Drug User Fee Act, the FDA must make a decision by February 28, 2021.

The NDA is supported by data from the phase 1/2 ARROW trial (NCT03037385), in which investigators are evaluating the safety and efficacy of pralsetinib in patients with RET fusion–positive non­–small cell lung cancer, RET-mutant MTC, RET fusion–positive thyroid cancer, and other RET-altered solid tumors. The trial was comprised of 2 parts: a dose-escalation phase and an expansion phase. In the expansion phase, participants are receiving pralsetinib at a dose of 400 mg once daily.

Pralsetinib elicited an objective response rate (ORR) of 74% in treatment-naïve patients with RET-mutant MTC (n = 19); the ORR was 60% in those who received previous treatment with an approved multikinase inhibitor (n = 53).²

Moreover, the median duration of response (DOR) had not yet been reached in either subgroup. Specifically, in those who received prior treatment, the DOR at 18 months was 90% (95% CI, 77%-100%). In the treatment-naïve subgroup, the majority, or 12 of 14, had responses that continued for up to 15 months.

Among 11 patients with RET fusion–positive thyroid cancer, the agent elicited an ORR of 91% (95% CI, 59%-100%); this was comprised entirely of partial responses (PRs).³ The remaining patients achieved stable disease; this translated to a disease control rate (DCR) of 100% (95% CI, 72%-100%). Responses to pralsetinib were observed to occur rapidly, within 1 to 2 months.

The data reported in the overall safety population of the trial (n = 354) proved to be consistent with previously reported findings.⁴ Here, the most commonly reported any-grade treatment-related TRAEs in the overall patient population included aspartate aminotransferase increase (31%), anemia (22%), alanine amintotransferase increase (21%), constipation (21%), hypertension (20%), and neutropenia (19%). Grade 3 or higher TRAEs included hypertension (10%), neutropenia (10%), and anemia (8%). The treatment discontinuation rate because of TRAEs was 4%.

Data from a cohort of the ongoing phase 1/2 trial were presented during the 2020 ASCO Virtual Scientific Program and showed that pralsetinib had broad and durable antitumor activity across several advanced solid tumors.

The data presented at the meeting focused on the basket study population of all-comers with RET alterations. Twenty-seven participants were enrolled to the subgroup; this included 13 patients with thyroid cancer and 14 with other solid tumor types.

Of patients with RET fusion–positive thyroid cancer, the median age was 63 years and 54% were male. Thirty-one percent of patients had an ECOG performance status of 0, 62% had a status of 1, and 8% had a score of 2. All participants had stage IV disease and 38% had brain metastases at baseline.

Moreover, 92% of patients had received previous treatment with systemic therapy, including radioactive iodine (92%), lenvatinib (Lenvima) or sorafenib (Nexavar; 54%), and cabozantinib (Cabometyx) or vandetanib (Caprelsa; 15%). The most common fusion partner for RET was CCDC6 in 46% of patients, followed by NCOA4 in 31% and others in 23%.

The RET all-comer population was comprised of patients with several tumor types, including colon (n = 3), mixed histology lung (n = 3), pancreatic (n = 3), cholangiocarcinoma (n = 2), ovarian (n = 1), neuroendocrine (n = 1), and thymus cancers (n = 1).

Among these participants with other tumor types, the median age was 54 years and 43% were male. Thirty-six percent of these patients had an ECOG performance status of 0, while 64% had a status of 1. The overwhelming majority, or 93%, had metastatic disease and 14% had brain metastases.

All of these patients had received previous treatment with systemic therapy, including chemotherapy (100%), and half received an additional anticancer therapy; 7% of patients received cabozantinib or vandetanib. The most common fusion partner in this population was CCDC6 in 29%, followed by KIF5B in 21%, and NCOA4 in 14%.

In the basket-study population, the most frequently reported toxicities included anemia (33%), increased aspartate aminotransferase (33%), decreased white blood cell counts (33%), hypertension (30%), increased alanine aminotransferase (26%), hyperphosphatemia (19%), and neutropenia (19%). No treatment discontinuations because of TRAEs were reported.

The priority review was granted at the same time that the FDA approved pralsetinib for use in adult patients with RET fusion–positive NSCLC.

References

1. Genentech announces FDA approval of Gavreto (pralsetinib) for the treatment of adults with metastatic RET fusion-positive non-small cell lung cancer. News release. Genentech. September 4, 2020. Accessed September 4, 2020. https://bwnews.pr/2QWJ4LM.
2. Blueprint Medicines announces the achievement of key portfolio milestones. News release. Blueprint Medicines Corportion. April 1, 2020. Accessed September 4, 2020. https://bit.ly/358ikQE.
3. Subbiah V. Hu MI, Gainor JF, et al. Clinical activity of the RET inhibitor pralsetinib (BLU-667) in patients with RET fusion+ solid tumors. J Clin Oncol. 2020;38(suppl 15):109. doi:10.1200/JCO.2020.38.15_suppl.109
4. Gainor JF, Curigliano G, Kim D-W, et al. Registrational dataset from the phase 1/2 ARROW trial of pralsetinib (BLU-667) in patients with advanced RET fusion+ non-small cell lung cancer (NSCLC). J Clin Oncol. 2020;38(suppl 15):9515. doi:10.1200/JCO.2020.38.15_suppl.9515