Final Efficacy and Safety Data From the Phase I/II ARROW Study of Pralsetinib

Somewhere inside about 1-2% of non-small cell lung cancers, two genes that absolutely should not be talking to each other are shaking hands - and that handshake is telling cells to grow like they've lost all sense of personal boundaries. The gene in question is RET, short for "rearranged during transfection" (scientists named it in the 1980s and clearly weren't thinking about SEO). When RET fuses with a partner gene like KIF5B or CCDC6 through a chromosomal rearrangement, the result is a chimeric protein that's permanently switched to "go" - no off button, no pause, just relentless cell growth signaling. It's like someone duct-taped the gas pedal to the floor of a car that also happens to be on fire.

Pralsetinib was designed to jam a wrench into that specific engine. And the final results from the ARROW trial, just published in the Journal of Clinical Oncology, show it did a pretty solid job.

The Numbers That Actually Matter

The ARROW study (Phase I/II, multi-cohort, open-label) enrolled patients with advanced RET fusion-positive NSCLC across treatment lines. With a data lock in May 2024 and a median follow-up of nearly four years (47.6 months), the final tally looks like this: median overall survival hit 44.3 months, and the overall response rate landed at 70.3% among patients with measurable disease. Median duration of response was 19.1 months, meaning tumors didn't just shrink - they stayed shrunk for a meaningful stretch (Besse et al., 2025).

For context, before selective RET inhibitors came along, these patients were stuck with platinum-based chemotherapy combos that topped out around 30-40% response rates. Jumping to 70% is the difference between "maybe this will work" and "this will probably work."

Who Gets RET Fusion Lung Cancer? Not Who You'd Expect

Here's where things get counterintuitive. RET fusion-positive NSCLC overwhelmingly hits people who have never smoked - over 60-80% of patients in studies are never-smokers, and they tend to be younger (under 60). That's roughly 4,000 Americans and 37,500 people worldwide each year who develop a lung cancer that has nothing to do with cigarettes, yet still carries the stigma of a "smoker's disease" (Choudhury & Drilon, 2020). These fusions also carry a nasty habit of spreading to the brain - up to 46% of patients develop brain metastases.

The Side Effect Situation

Let's not pretend this is a free lunch. Ninety-five percent of patients on pralsetinib experienced treatment-related adverse events, with 66% hitting grade 3 or higher. The greatest hits included elevated liver enzymes (AST up in 46%, ALT in 35%), anemia (43%), and hypertension (27%). Three patients died from treatment-related causes - pneumonia in two cases, and interstitial lung disease with rhabdomyolysis in one. Serious, but for an advanced cancer drug, the safety profile stayed within a manageable range with no new signals emerging even after years of follow-up (Besse et al., 2025).

The Bigger Picture: A Crowded (But Welcome) Party

Pralsetinib isn't alone in the RET inhibitor space. Selpercatinib (Retevmo) earned a phase III win in the LIBRETTO-431 trial, delivering 24.8 months of progression-free survival versus 11.2 months for chemo-plus-pembrolizumab as first-line therapy, published in the New England Journal of Medicine (Solomon et al., 2023). Having two validated selective RET inhibitors gives oncologists options - especially important because resistance eventually develops (median duration of response hovers around 11-19 months depending on the drug and line of therapy).

Meanwhile, pralsetinib's commercial journey has been bumpy. Roche walked away from its partnership with Blueprint Medicines in 2023, and the medullary thyroid cancer indication was voluntarily withdrawn from the U.S. market. Rigel Pharmaceuticals now holds the torch. But the ARROW data stands on its own: this drug works in RET fusion-positive NSCLC, and the final dataset confirms it.

Why This Matters Beyond the Data Tables

A decade ago, RET fusions in lung cancer were an academic curiosity - identifiable, but untargetable. Patients got the same platinum doublets as everyone else and hoped for the best. The arrival of selective RET inhibitors turned a molecular footnote into a treatment strategy. The ARROW trial's final readout, spanning nearly five years of follow-up, closes the book on pralsetinib's foundational evidence: durable responses, meaningful survival, and a side effect profile that's tough but tolerable. For the subset of lung cancer patients whose tumors run on a rogue RET fusion, that's not nothing. That's the whole point.

References

1. Besse B, Subbiah V, Curigliano G, et al. Final efficacy and safety data from the phase I/II ARROW study of pralsetinib in patients with advanced RET fusion-positive NSCLC. J Clin Oncol. 2025. DOI: 10.1200/JCO-25-01489

2. Gainor JF, Curigliano G, Kim DW, et al. Pralsetinib for RET fusion-positive non-small-cell lung cancer (ARROW): a multi-cohort, open-label, phase 1/2 study. Lancet Oncol. 2021;22(7):959-969. PMID: 34118197

3. Griesinger F, Curigliano G, Thomas M, et al. Safety and efficacy of pralsetinib in RET fusion-positive non-small-cell lung cancer including as first-line therapy: update from the ARROW trial. Ann Oncol. 2022;33(11):1168-1178. PMID: 35973665

4. Solomon BJ, Drilon A, Lin JJ, et al. First-line selpercatinib or chemotherapy and pembrolizumab in RET fusion-positive NSCLC. N Engl J Med. 2023;389(20):1839-1850. PMID: 37870973

5. Choudhury NJ, Drilon A. Decade in review: a new era for RET-rearranged lung cancers. Transl Lung Cancer Res. 2020;9(6):2571-2580. PMCID: PMC7815364

Disclaimer: The image accompanying this article is for illustrative purposes only and does not depict actual experimental results, data, or biological mechanisms.