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Pralsetinib Shows Promise in Diverse RET Fusion-Positive Cancers

— An ORR of 57% supports results previously observed in NSCLC and thyroid cancer

MedpageToday
Photo of a bottle of Pralsetinib.

The highly selective RET inhibitor pralsetinib (Gavreto) achieved "rapid, robust, and durable" anti-tumor activity in patients with a variety of RET fusion-positive solid tumors, an analysis of the showed.

Among 23 patients with a dozen different RET fusion-positive solid tumor types, the overall response rate (ORR) was 57%, with three patients achieving a complete response and 10 achieving a partial response, reported Vivek Subbiah, MD, of the University of Texas MD Anderson Cancer Center in Houston, and colleagues in .

The median duration of response (DOR) was 11.7 months at a median follow-up of 26.7 months, and DOR rates were 69% at 6 months and 39% at 12 months. Of the 13 patients with a response, DOR was ≥6 months for nine, ≥18 months for two, and ≥24 months for one. Median time to response was 1.9 months at data cutoff, with four patients having ongoing responses.

Median progression-free survival (PFS) was 7.4 months at a median follow-up of 28.5 months, and PFS rates were 60% at 6 months and 41% at 12 months. Overall survival (OS) was 13.6 months at a median follow-up of 23.5 months, and OS rates were 78% at 6 months and 54% at 12 months.

"In combination with the robust activity seen in patients with NSCLC [non-small cell lung cancer] 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 tumor types with differing histology," Subbiah and team wrote. "Overall, these data highlight the need for broad RET testing, preferably by NGS [next-generation sequencing], to identify candidates who may benefit from treatment with pralsetinib."

The FDA approved pralsetinib for in September 2020, and for adult and pediatric patients ages 12 and older with advanced or metastatic RET-mutant thyroid cancer in December 2020. Both approvals were based on earlier results from the ARROW trial, which demonstrated ORRs ranging from 57% in patients with RET fusion-positive NSCLC previously treated with platinum chemotherapy, to 89% in patients with RET fusion-positive thyroid cancer, with a duration of response of at least 6 months in most responders.

The current analysis was designed to see if there is a benefit to pralsetinib beyond NSCLC and thyroid cancer. Cancer diagnoses in the efficacy-evaluable population included pancreatic cancer (four patients); cholangiocarcinoma, neuroendocrine cancer, and sarcoma (three each); colorectal cancer, small-cell lung cancer, and head and neck cancer (two each); and malignant mesenchymal tumor, mixed sarcoma and adenocarcinoma, malignant isolated fibroma, sweat gland cancer, and salivary duct cancer (one each).

Confirmed tumor responses were observed in:

  • Four patients with pancreatic cancer (including one complete response)
  • Two patients with cholangiocarcinoma
  • Two patients with sarcoma (one complete response)
  • Two patients with neuroendocrine cancer
  • One patient each with head and neck cancer and unknown primary tumor (complete response)

The other patient with cholangiocarcinoma had a single timepoint response before discontinuing treatment due to an adverse event.

Furthermore, all but two patients experienced tumor shrinkage.

As for safety, the most common grade ≥3 treatment-related adverse events (TRAEs) were neutropenia (31%) and anemia (14%). Overall, 17 patients (59%) had short-term dose interruptions due to TRAEs, while 13 patients (45%) had permanent dose reductions.

ARROW enrolled 587 patients from March 2017 to October 2021, 29 of whom had RET fusion-positive solid tumors, excluding NSCLC and thyroid cancer.

Overall, 28 patients received a starting dose of pralsetinib 400 mg daily, and one patient received a starting dose at 200 mg/100 mg twice daily but transitioned to 400 mg daily after 3.4 months. At the time of data cutoff, four patients remained on treatment, and 25 patients had discontinued treatment, mostly due to disease progression.

Among the 23 patients evaluable for efficacy, median age was 53 years, 61% were women, 87% had metastatic disease, and 87% had received prior therapies at baseline.

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    Mike Bassett is a staff writer focusing on oncology and hematology. He is based in Massachusetts.

Disclosures

The ARROW study was supported by Blueprint Medicines and F. Hoffmann-La Roche.

Subbiah reported relationships with AbbVie, Agensys, Alfasigma, Altum, the American Society of Clinical Oncology, Amgen, Bayer, BERG Health, Blueprint Medicines, Boston Biomedical, Boston Pharmaceuticals, Celgene, D3 Bio, Daiichi-Sankyo, Dragonfly Therapeutics, Eli Lilly, the European Society for Medical Oncology, Exelixis, Fujifilm, GlaxoSmithKline, Helsinn Healthcare, Idera Pharmaceuticals, Incyte, Inhibrx, Loxo Oncology, MedImmune, MultiVir, NanoCarrier, the National Comprehensive Cancer Network, the National Cancer Institute's Cancer Therapy Evaluation Program, Northwest Biotherapeutics, Novartis, PharmaMar, Pfizer, QED Therapeutics, R-Pharm US, Relay Therapeutics, Roche/Genentech, Takeda, Turning Point Therapeutics, the MD Anderson Cancer Center, Vegenics, and Medscape.

Co-authors also reported multiple relationships with industry.

Primary Source

Nature Medicine

Subbiah V, et al "Pan-cancer efficacy of pralsetinib in patients with RET fusion-positive solid tumors from the phase 1/2 ARROW trial" Nat Med 2022; DOI: 10.1038/s41591-022-01931-y.