Pralsetinib Active Across RET+ Tumor Types and Gains FDA Review


RET inhibitor pralsetinib induced responses in a number of patients with rare and difficult to treat RET fusion–positive solid tumors.

Vivek Subbiah, MD

Vivek Subbiah, MD

Vivek Subbiah, MD

RET inhibitor pralsetinib (BLU-667) induced responses in a number of patients with rare and difficult to treat RET fusion—positive solid tumors. Data from a cohort of the ongoing phase 1/2 ARROW trial (NCT03037385) were presented during the 2020 American Society of Clinical Oncology (ASCO) Virtual Scientific Program.1

“Pralsetinib has broad and durable antitumor activity with multiple advanced solid tumors,” said Vivek Subbiah, MD, associate professor in the Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center.

RET fusions have been identified as oncogenic drivers for multiple solid tumor types. In thyroid cancers specifically, RET fusions can be found in about 10% to 20% of papillary thyroid cancers (PTCs), mutations are found in about 50% of sporadic medullary thyroid cancers (MTCs), and germline mutations as a part of multiple endocrine neoplasia type 2 (MEN2) syndrome in almost 100% of MTCs. RET alterations are also often found in rare and hard-to-treat cancers, including salivary gland tumors and cholangiocarcinoma.

Subbiah explained that standard treatments have shown limited efficacy in patients with RET fusion—positive solid tumors. Additionally, patients with RET-altered non—small cell lung cancer (NSCLC)—which accounts for 1% to 2% of all NSCLCs—have seen poor outcomes from treatment with immunotherapy, making this an unmet medical need that can be addressed with targeted therapy. “Genome-driven precision oncology has altered the landscape of multiple solid and hematologic malignancies. Recent tumor-agnostic drug approvals have resulted in a paradigm shift in a paradigm shift in cancer treatment away from organ/histology–specific indications to biomarker-guided tumor-agnostic approaches,” he stated.

Pralsetinib, a specific and highly selective RET inhibitor targeting both RET fusions and mutations, is being positioned to fill this need for various RET-altered solid tumors. As such, Blueprint Medicines submitted a rolling New Drug Application (NDA) to the FDA and an application to the European Medicines Agency (EMA) as a potential treatment of patients with RET fusion—positive NSCLC.2 The NDA was accepted by the FDA and granted a priority review with an action date of November 23, 2020. In the European Union, the EMA validated the application.3

"The use of targeted therapies for molecularly defined subsets of patients is fundamentally altering the treatment of non-small cell lung cancer and, similar to oncogenes like EGFR and ALK, RET is a proven driver and promising therapeutic target," Justin Gainor, MD, director of the Center for Thoracic Cancers and Targeted Immunotherapy at Massachusetts General Hospital Cancer Center and an investigator on the ARROW trial, said in a statement. "The ARROW trial results presented today during the ASCO virtual meeting showed that patients with RET fusion—positive lung cancer treated with the selective RET inhibitor pralsetinib had durable responses. In addition to supporting the development of pralsetinib across a broad population, these data highlight the urgency to test [patients with] lung cancer with next-generation sequencing so that eligible patients may be identified for treatment."

Further, Blueprint Medicines also plans to submit an NDA for pralsetinib as treatment of patients with advanced RET-mutant and RET fusion—positive thyroid cancer to the FDA in June 2020 for review under the Real-Time Oncology Review pilot program.3

Promising findings in both of these patient populations have already been demonstrated from prior findings released from the ARROW trial. An objective response rate (ORR) of 73% was reported in patients with treatment-naïve RET fusion—positive NSCLC and 61% in patients who previously received platinum-based chemotherapy.4 Among patients with RET-mutant MTC, an ORR of 74% was seen in treatment-naïve patients and 60% in previously treated patients.2

ARROW is a first-in-human trial to examine the safety and efficacy of the RET inhibitor. The phase 2 design of the study included cohorts for patients with RET fusion—positive NSCLC, RET mutation—positive MTC, and those with other RET fusion—positive solid tumors. Eligible patients were those with advanced solid tumors harboring RET alterations and no other driver mutations. Treatment was administered at 400 mg orally once daily.

Primary end points of the phase 2 portion include centrally reviewed ORR per RECIST v1.1 criteria and safety.

All-Comer RET Population Findings

The ASCO presentation focused on the basket study population of all-comers with RET alterations.1 Twenty-seven patients were included in the subgroup, including 13 with thyroid cancer and 14 with other solid tumor types.

Among the patients with RET fusion—positive thyroid cancer, consisting of 12 with PTC and 1 with poorly differentiated thyroid cancer, the median age was 63 (range, 23-74) and more than half were male (54%). Patients had an ECOG performance status of 0 (31%), 1 (62%), or 2 (8%), and all had stage IV disease, with 38% having brain metastases at baseline.

Ninety-two percent had received prior systemic therapy, including radioactive iodine (RAI) treatment in all 92%, lenvatinib (Lenvima) or sorafenib (Nexavar) in 54%, and cabozantinib (Cabometyx) or vandetanib (Caprelsa) in 15%. The most common fusion partner for RET was CCDC6 in 46%, followed by NCOA4 in 31% and others in 23%.

Other tumor types included in the RET all-comer population were colon, mixed histology lung, and pancreatic (n = 3 each); cholangiocarcinoma (n = 2); and ovarian, neuroendocrine, and thymus cancers (n = 1 each).

Among the patients with other tumor types, the median age was 54 years (range, 31-71) and 43% were male. Patients had an ECOG performance status of 0 (36%) or 1 (64%) and all but 1 patient had metastatic disease (93%), including brain metastasis in 14%.

All patients had received prior systemic therapy, including chemotherapy (100%), 50% received additional anticancer therapy, and 1 patient (7%) received cabozantinib or vandetanib. The most common fusion partner was CCDC6 in 29% followed by KIF5B in 21% and NCOA4 in 14%.

The ORR was 91% (95% CI, 59%-100%) in 11 evaluable patients with RET fusion—positive thyroid cancer, consisting of all partial responses (PRs). The remaining patient had stable disease, amounting to a disease control rate of 100% (95% CI, 72%-100%). “Most of [these] patients [had] papillary thyroid cancer and pralsetinib is active in these patients regardless of the fusion partner,” Subbiah said, adding that their treatment duration was prolonged, with 7 still on treatment. Additionally, responses occurred quickly within 1 to 2 months.

In the group of patients with other RET fusion—positive solid tumors, among 12 evaluable patients, the ORR was 50% (95% CI, 21%-79%) consisting of all PRs. Stable disease was also achieved by 5 patients, for a disease control rate of 92% (95% CI, 62%-100%).

Responses were seen regardless of fusion partner and in heavily pretreated patients. Notably, all 3 patients with pancreatic adenocarcinoma and both patients with cholangiocarcinoma had a PR. Treatment is ongoing for 6 patients in the subgroup.

Investigators found that safety in this cohort was consistent with findings from 354 patients treated with the RET inhibitor. As reported in a poster at the ASCO meeting, the most common any-grade treatment-related adverse events (TRAEs) in the overall patient population were aspartate aminotransferase increase (31%), anemia (22%), alanine aminotransferase increase (21%), constipation (21%), hypertension (20%), and neutropenia (19%). Common grade ≥3 TRAEs were hypertension (10%), neutropenia (10%), and anemia (8%). No discontinuations due to TRAEs were reported.5

Among the RET all-comers population, the most frequent AEs, which were mostly grade 1/2, included anemia (33%), increased aspartate aminotransferase (33%), decreased white blood cell counts (33%), hypertension (30%), increased alanine aminotransferase (26%), hyperphosphatemia (19%), and neutropenia (19%). The treatment duration was up to 23.5 months with a median relative dose intensity of 96%.

Subbiah urged that all patients with cancer should receive genomic testing.1 “The key message here I would like to tell you in a personal pitch is that we need to genomically test all patients with cancer and look for these rare alterations. Cancer is a genetic disease and if we are serious about treating cancer, we need to have every bit of intelligence, and genomics should be a part of therapy.”


  1. 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):109. doi:10.1200/JCO.2020.38.15_suppl.109
  2. Blueprint Medicines announces top-line data for pralsetinib and initiates rolling nda submission to FDA for the treatment of patients with RET fusion-positive non-small cell lung cancer. News release. Blueprint Medicine Corporation. January 8, 2020. Accessed May 31, 2020.
  3. Blueprint Medicines Announces Data Presentations at ASCO20 Highlighting Deep, Durable Clinical Activity and Well-Tolerated Safety Profile of Pralsetinib Across Broad Range of RET Fusion-Positive Tumors. News release. Blueprint Medicines Corporation. May 29, 2020. Accessed May 31, 2020.
  4. Blueprint Medicines announces the achievement of key portfolio milestones. News release. Blueprint Medicines Corporation. April 1, 2020. Accessed May 31, 2020.
  5. Gainor JF, Curigliano G, Kim DW, et al. Registrational dataset from the phase I/II ARROW trial of pralsetinib (BLU-667) in patients (pts) with advanced RET fusion+ non-small cell lung cancer (NSCLC). J Clin Oncol. 2020;38(suppl):9515. doi:10.1200/JCO.2020.38.15_suppl.9515

<<< 2020 ASCO Virtual Scientific Program

Related Videos
Sangeeta Goswami, MD, PhD, of The University of Texas MD Anderson Cancer Center
Pasi A. Jänne, MD, PhD, discusses an exploratory analysis from the FLAURA2 trial of osimertinib plus chemotherapy in treatment-naive, EGFR-mutant NSCLC.
Andrew Ip, MD
Arya Amini, MD
Adrianna Masters, MD, PhD,
Chul Kim, MD, MPH
Andrew Ip, MD
In this final episode of OncChats: Assessing the Promise of AI in Oncology, Toufic A. Kachaamy, MD, and Douglas Flora, MD, LSSBB, FACCC, discuss a roadmap of artificial intelligence (AI) advances in the next 5 to 10 years.
In this eighth episode of OncChats: Assessing the Promise of AI in Oncology, Toufic A. Kachaamy, MD, and Douglas Flora, MD, LSSBB, FACCC, explain how artificial intelligence tools are being developed to match the right patient to the right drug on the right clinical trial.
In this seventh episode of OncChats: Assessing the Promise of AI in Oncology, Toufic A. Kachaamy, MD, and Douglas Flora, MD, LSSBB, FACCC, discuss how artificial intelligence tools may be utilized to improve wait time for treatment, to provide more time for provider-patient interactions, and more.