Pralsetinib Shows Positive Phase 1/2 Results in RET Fusion+ NSCLC

Updated analysis from the phase 1/2 ARROW study evaluating pralsetinib in patients with RET fusion-positive non–small cell lung cancer showed the agent to be well tolerated and to elicit clinical activity at a dose of 400 mg daily.

Treatment with pralsetinib (Gavreto) was safe and produced durable response rates in patients with RET fusion-positive non–small cell lung cancer (NSCLC), according to findings or the phase 1/2 ARROW trial (NCT04222972) published in the Annals of Oncology.

Among 54 of the 75 treatment-naive patients, their overall response rate (ORR) was 72% (95% CI, 60%-82%) and 59% for 80 of the 130 patients with prior platinum-based chemotherapy (95% CI, 50%-67%).

Tumor shrinkage was observed in all of the treatment-naive patients and in 97% of patients with prior platinum-based chemotherapy. Additionally, the median progression-free survival (PFS) was 13.0 and 16.5 months, respectively.

“In this updated analysis of patients with RET fusion-positive NSCLC from the ARROW study, pralsetinib administered at a 400 mg [daily] starting dose was generally well tolerated and demonstrated clinical activity in all reported treatment groups, consistent with previous findings,” wrote study authors led by Frank Griesinger Department of Hematology and Oncology, Pius-Hospital, University of Oldenburg, Oldenburg, Germany.

A total of 281 patients with RET fusion-positive NSCLC were enrolled into the multi-cohort, multicenter, open-label, phase 1/2 ARROW trial between March 17, 2017, the data cut-off date of November 6, 2020. Investigators aimed to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and efficacy of pralsetinib in patients with advanced RET-altered tumors.

Phase 1 of the trial used a dose-escalation design to evaluate pralsetinib 30-600 mg. The determined recommended phase 2 dose of the study was 400 mg every day. In phase 2, pralsetinib 400 mg daily was evaluated in multiple expansion groups defined by disease type and treatment history.

Pralsetinib was administered at 400 mg daily and patients continued therapy until disease progression, intolerance, consent withdrawal, or investigator’s decision. Dose reductions due to adverse events (AEs) below 100 mg daily were not permitted. Additionally, dose interruptions due to AEs for greater than 28 days were not allowed.

Patients were eligible for enrollment in the study if aged 18 years and older with unresectable, locally advanced or metastatic solid tumors, a pathologically or genetically documented RET fusion or mutation, an ECOG performance status of 0-2, and baseline measurable disease as per RECIST version 1.1.

In the RET fusion-positive NSCLC cohorts of the study, eligible patients must have had a documented RET fusion as determined by local testing of tumor or circulating tumor nucleic acid (ctDNA) in blood. Regardless of their eligibility for standard platinum-based chemotherapy, treatment-naive patients with RET fusion-positive NSCLC were enrolled following a protocol amendment on 11 July 2019.

The median age for all patients enrolled with RET fusion-positive NSCLC (n = 233) was 60 years (range, 26-87). Less than half of the patients were male (n = 111; 48%), 52% were White, 39% were Asian, and the remaining 9% were other/unknown. Thirty-six percent of patients were current or former smokers compared with 62% who had never smoked. Most patients (64%) had an ECOG performance status of 1, 37% had brain metastases, 70% had KIF5B fusions, 18% had CCDC6 fusions, and about 12% had NCOA4 or other fusions.

Investigators assessed the co-primary end points of ORR, including complete response (CR) or partial response (PR), in the phase 2 portion of the study. Secondary end points were duration of response (DOR), time from first response until disease progression or death, clinical benefit rate (CBR), disease control rate (DCR), PFS, overall survival, and correlation of RET gene alteration and efficacy.

FIndings showed that in the ITT population, treatment-naive patients with RET fusion-positive NSCLC (n = 75) had an ORR of 72% (95% CI, 60%-82%) with a median time to first response of 1.8 months (range, 0.9-6.1 months). CR was seen in 4 patients (5%) while 50 (67%) had a PR, 14 (19%) had stable disease, 5 (7%) had progressive disease, and 2 (3%) were not assessable.

For the treatment-naive patients, the median DOR was not reached vs 22.3 months for patients who had received prior platinum-based chemotherapy after a median follow-up of 7.4 months (95% CI, 6.4-9.5 months). However, 84% (95% CI, 73%-95%) and 54% (95% CI, 34%-74%) of patients were responding at 6 months and 12 months, respectively. The DCR was 91% (95% CI, 82%-96%) and the CBR was 80% (95% CI, 69%-88%).

Further, the median PFS was 13.0 vs 16.5 months, respectively, after a median follow-up of 9.2 months (95% CI, 8.6-11.0 months). Seven of the 10 patients with measurable intracranial metastases had intracranial response (95% CI, 35%-93%), and all had received prior systemic treatment.

Regarding safety, the most common grade 3-4 treatment-related adverse events (TRAEs) in the treatment-naive patients with RET fusion-positive NSCLC who initiated pralsetinib by the data cut-off (n = 116), were neutropenia (18%), hypertension (10%), increased blood creatine phosphokinase (9%), and lymphopenia (9%). A total of 7% (20/281) of patients discontinued treatment due to TRAEs.

Currently, the confirmatory phase 3 AcceleRET Lung study (NCT04222972) is ongoing and examining pralsetinib vs standard of care in the first-line setting of this patient population. Experts hope that findings from this trial will further support the use of pralsetinib for patients with RET fusion-positive NSCLC in the frontline.

“In conclusion, we show that orally administered once daily pralsetinib produces a robust ORR, including intracranial activity and durable PFS, in patients with advanced RET fusion-positive NSCLC who are treatment-naive or refractory to standard-of-care chemotherapy. These results show the importance of early comprehensive biomarker testing that includes fusions for all patients with metastatic NSCLC before treatment initiation to inform optimal health care decisions,” concluded the study authors.


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. doi:10.1016/j.annonc.2022.08.002