Results from the precision oncology ARROW, phase I/II study of the highly selective RET inhibitor pralsetinib identify the RET receptor tyrosine kinase as a tissue-agnostic target and potential of pralsetinib as a well-tolerated treatment option with rapid, robust, and durable antitumour activity in patients with different RET fusion positive solid tumours. ARROW was conducted in patients with medullary thyroid cancer, RET altered non-small cell lung cancer (NSCLC) and other RET altered solid tumours. After recent approvals of pralsetinib in patients with RET altered NSCLC and thyroid cancers and publications of these data, Dr. Vivek Subbiah of The University of Texas MD Anderson Cancer Center, Houston, TX, US and colleagues published on 12 August 2022 in the Nature Medicine interim data on the efficacy and safety of pralsetinib in prospectively identified patients with other different RET fusion positive solid tumours.
The authors wrote in the background that RET fusions and mutations induce oncogenic transformation, leading to the aberrant activation of RET receptor tyrosine kinase. RET fusions can be found in 1–2% of NSCLC, approximately 20% of papillary thyroid cancers and <1% of many other solid tumours, including ovarian, pancreatic, salivary and colorectal cancers.
Pralsetinib is a selective RET inhibitor that potently targets RET kinases, including RET fusion proteins. The recommended phase 2 dose of 400 mg once daily orally administered pralsetinib was determined in phase I of the ARROW study. Based on the results from the registrational phase I/II ARROW study, pralsetinib was approved in several countries for treatment of metastatic RET fusion positive NSCLC, advanced or metastatic RET mutated medullary thyroid cancer and RET fusion positive thyroid cancer.
Since the approvals of pralsetinib and selpercatinib in NSCLC and thyroid cancer, biomarker testing for RET alterations is recommended in treatment guidelines for patients with these tumour types. However, this is not standard of care across all diseases where RET alterations are recognised as oncogenic drivers.
In total, 29 patients with 12 different types of RET fusion positive solid tumours, excluding NSCLC and thyroid cancer, who had previously received or were not candidates for standard therapies, were enrolled. The most common RET fusion partners in 23 efficacy-evaluable patients were CCDC6 (26%), KIF5B (26%) and NCOA4 (13%).
Overall response rate (ORR), the primary endpoint, was 57% (95% confidence interval, 35–77) among these patients. Responses were observed regardless of tumour type or RET fusion partner. Median duration of response, progression-free survival and overall survival were 12 months, 7 months and 14 months, respectively.
The most common grade ≥3 treatment-related adverse events (TRAEs) were neutropenia (31%) and anaemia (14%). The safety profile reported in this analysis is consistent with previously reported results in patients with RET fusion positive NSCLC and thyroid cancer from the ARROW study, with no new safety signals identified, and no effect of pralsetinib on QT interval was observed.
The authors commented that in this phase I/II study of pralsetinib in patients with advanced or metastatic RET fusion positive solid tumours, almost all of whom were previously treated with systemic treatment, pralsetinib showed robust and durable antitumour activity regardless of tumour type or RET fusion partner. RET fusions defined a unique subset of alterations across multiple tumour types targeted by pralsetinib, validating RET as a tissue-agnostic target.
In this patient group, whose disease was resistant to prior treatments where available, treatment with pralsetinib resulted in an ORR of 57% across 7 tumour types, and clinical benefit was reported in 70% of patients by blinded independent central review. This compares to an ORR of 61% and 70% in patients with RET fusion positive NSCLC who received prior platinum treatment and no prior systemic treatment, respectively, and an ORR of 89% for patients with RET fusion positive thyroid cancer in previously published data on the ARROW study.
Despite the small number of patients, responses were seen in all 4 patients with pancreatic cancer, including an ongoing complete response with treatment duration of 33.1 months, as well as in 2 of the 3 patients with cholangiocarcinoma, including a patient who received treatment for over 20 months after a best response of progressive disease on all 3 prior treatment lines. These are encouraging findings because these tumour types are difficult to treat.
In ARROW, responses were seen in treatment-naive patients who were not candidates for standard treatments and in patients who had received several prior lines of treatment, highlighting the need for targeted treatments across a range of tumour types for patients who currently have no standard of care and for those who have exhausted all other options.
ARROW is a single-arm study with no comparator group. The safety population for the cohort analyzed in the latest report included a small heterogeneous number of patients; despite this, all but 2 patients included in the efficacy-evaluable population experienced a tumour shrinkage. In combination with the robust activity seen in patients with NSCLC and thyroid cancer in the ARROW study, these data further support the potential of pralsetinib to address the unmet medical need across a broad range of RET altered tumour types with different histology.
The authors concluded that overall, these data highlight the need for broad RET testing, preferably by next-generation sequencing, to identify candidates who may benefit from treatment with pralsetinib.
Enrolment of patients with other RET fusion positive solid tumours in ARROW is ongoing.
Subbiah V, Cassier PA, Siena S, et al. Pan-cancer efficacy of pralsetinib in patients with RET fusion–positive solid tumors from the phase 1/2 ARROW trial. Nature Medicine 2022;28:1640-1645.