Targeted Therapy Improves Long-Term Outcomes for Patients with Rare Mutations Driving Lung Cancer

Mass General Brigham Cancer Institute study found that patients with advanced RET fusion-positive lung cancer showed robust and durable responses.

In some non-small cell lung cancers (NSCLCs), changes to the RET gene (known as RET fusions) can drive tumor growth. In a phase 1/2 clinical study with a 42-month-long follow-up period, researchers from Mass General Brigham Cancer Institute evaluated the long-term efficacy and safety of the FDA-approved drug pralsetinib, which targets RET. Investigators found that treatment led to durable responses with manageable safety profiles in 281 patients with advanced or metastatic RET fusion-positive NSCLCs. Results are published in Journal of Clinical Oncology.

“Before selective RET inhibitors were developed, the expected overall survival for advanced RET fusion-positive NSCLC was roughly between 4 and 11 months. Now we show that pralsetinib can extend the median survival rate to 44 months,” said senior author Justin Gainor, MD, Division Chief, Solid Tumor Medical Oncology at Mass General Brigham Cancer Institute. “Our findings reinforce the importance of early biomarker testing, including testing for gene fusions, in all metastatic NSCLC patients to guide treatment.”

The current study used data from the ARROW study — an open-label, multi-center phase 1/2 clinical trial that enrolled 281 patients with advanced RET fusion-positive NSCLC — and an additional 42 months of follow-up data. The results demonstrated that the overall response rate to pralsetinib was 78% in patients who hadn’t received prior treatment, 63% for patients who had previously undergone chemotherapy, and 73% patients with brain metastases.

Patients with the RET fusion gene partners CCDC6 and KIF5B had high overall response rates to treatment. The median duration of response was longer in patients bearing CCDC6-RET (47.9 months) when compared to those with KIF5B-RET (13.1 months). Common treatment-related adverse effects included anemia, hypertension and reduced neutrophil count, which led to discontinued treatment in 10% of patients and dose reduction in 51%. Three patients died from treatment-related causes.

The authors note that pralsetinib’s safety profile is manageable and that the drug did not cause hypersensitivity in patients exposed to prior immunotherapies, an effect sometimes induced by other RET inhibitors. Further research is needed to understand the mechanisms of resistance to RET inhibitors.

Authorship: In addition to Gainor, authors include Benjamin Besse, Vivek Subbiah, Giuseppe Curigliano, Daniel W. Bowles, Robert C. Doebele, Aaron S. Mansfield, Christina S. Baik, Gilberto de Lima Lopes, Luis Paz-Ares, Matthew H. Taylor, Daniel S. W. Tan, Guzman Alonso, Shirish M. Gadgeel, Gregory P. Kalemkerian, Sai-Hong Ignatius Ou, Anthonie J. van der Wekken, Carlos R. Becerra, Makenzi Evangelist, Frank Griesinger, Stephen V. Liu, Yanyan Lou, Julien Mazières, Jason M. Melear, Mohit Narang, Ashish Saxena, Michael Thomas, Sophia Wang, Amber Thomassen, Dae Ho Lee, and Dong-Wan Kim.

Disclosures: Wekken and Thomassen are employees of Rigel Pharmaceuticals, Inc.

Funding: The study was supported by Blueprint Medicines and Genentech/Roche.

Paper cited: Besse B et al. “Final Efficacy and Safety Data From the Phase 1/2 ARROW Study of Pralsetinib in Patients With Advanced RET Fusion-Positive Non-Small Cell Lung Cancer (NSCLC)” JCO DOI: 10.1200/JCO-25-01489