Clinical Summary:

• Design/Population: The phase 3 AcceleRET-Lung trial randomized approximately 230 treatment-naive patients with advanced RET fusion–positive non-small cell lung cancer to receive either pralsetinib 400 mg daily or histology-specific chemotherapy with or without pembrolizumab. 
• Key Outcomes: The study met its primary endpoint, demonstrating significantly improved progression-free survival with pralsetinib versus chemotherapy with or without pembrolizumab. Objective response rates were also higher with pralsetinib, with longer duration of response. 
• Clinical Relevance: These findings confirm pralsetinib as superior to chemotherapy-based treatment in the first-line setting for RET fusion-positive NSCLC and support current guideline recommendations favoring selective RET inhibition. 

Sanjay Popat, PhD, FRCP, medical oncologist at The Royal Marsden Hospital in London, England, discusses results from the phase 3 AcceleRET-Lung trial evaluating first-line pralsetinib versus standard-of-care histology-specific chemotherapy with or without pembrolizumab in patients with advanced RET fusion-positive non-small cell lung cancer. Approximately 230 patients were randomized, including patients with asymptomatic active brain metastases, to assess whether selective RET inhibition could improve outcomes compared with conventional frontline treatment.

The study met its primary endpoint, demonstrating a statistically significant and clinically meaningful improvement in progression-free survival with pralsetinib compared with chemotherapy with or without pembrolizumab. Response rates were also higher with pralsetinib, with more durable responses observed. These findings reinforce current recommendations supporting selective RET inhibitors as first-line therapy for RET fusion–positive NSCLC.

Dr Popat presented these findings at the 2026 American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago, Illinois.

Transcript:

It’s Sanjay Popat, a medical oncologist at The Royal Marsden Hospital in London, England. Here at the ASCO 2026 Annual Meeting, I was delighted to present results of the AcceleRET-Lung clinical trial.

This is a randomized phase 3 trial of pralsetinib versus standard-of-care histology-specific chemotherapy with or without pembrolizumab in patients with advanced non-small cell lung cancer with RET fusions.

We know that pralsetinib already has full FDA approval for patients with RET-positive non-small cell lung cancer on the basis of the ARROW study, which is a single-arm phase 1/2 trial. However, we haven’t really established its role in the frontline setting very well, particularly against what we might envisage as standard treatment, which at the time of enrollment was chemotherapy with or without immunotherapy.

The study was designed to evaluate that further. Around 230 patients were randomized 1:1 to receive either pralsetinib, a selective RET inhibitor given at the standard dose of 400 mg daily, or standard-of-care histology-specific chemotherapy with or without pembrolizumab.

Patients were eligible if they had advanced non-small cell lung cancer with proven RET fusions. They were eligible if they had asymptomatic active brain metastases and, of course, could not have had any prior systemic therapy and had an ECOG performance status of 0 or 1.

Patients randomized to the control arm were eligible to cross over to the pralsetinib arm on progression. The primary endpoint of the study was progression-free survival, with key secondary endpoints including response rate, safety, and overall survival.

The trial recruited globally, predominantly from Europe, but was a global study and was typical of a RET-positive population, relatively young compared with most lung cancer studies and nearly exclusively adenocarcinoma. It was a slightly poorer prognostic group than typically seen in RET studies. About 30% of patients had brain metastases going into the study, and 40% of patients had a history of tobacco use as current or former smokers.

When we looked at the primary endpoint of the study, the primary endpoint was met. There was a clinically meaningful and statistically significant improvement in progression-free survival for pralsetinib, with a hazard ratio of 0.59 and a median progression-free survival of around 18.6 months, compared with around 9 months for standard chemotherapy with or without pembrolizumab. This was maintained when comparing pralsetinib with the subgroup of patients who received chemotherapy plus pembrolizumab.

When we looked at key secondary endpoints, we looked at response rate, and this was statistically significantly higher for pralsetinib compared with chemotherapy plus or minus pembrolizumab, around 65% compared with 40%. This underpinned a much longer duration of response as well for pralsetinib compared with the control arm.

Overall survival was very immature at the time of this analysis. This analysis was the final analysis because the sponsor terminated the study at 99% of accrual. Overall survival was not significantly different between the 2 arms, which was underpinned by the immaturity of the data, with only 30% of expected events having occurred, and also because 34% of patients in the control arm crossed over into the investigational arm, confounding the analysis.

When we looked at safety, we saw that safety was as expected. Most adverse events were grade 1 or grade 2. The predominant grade 3 or higher adverse events were hypertension, anemia, neutropenia, and pneumonia. We observed very low rates of grade 3 or higher ALT elevation and QTc prolongation, both less than 4%.

When we looked further, we identified an emerging safety signal during the study. There were 8 deaths from serious infection in the pralsetinib arm compared with none in the chemotherapy arm. This prompted an urgent protocol amendment urging investigators to be vigilant for infection and to dose reduce or discontinue treatment depending on the severity of infection identified. After implementation of this amendment, there were no further deaths due to infection among pralsetinib-treated patients. When we looked at the sponsor’s global database of all pralsetinib-treated patients after implementation of this safety measure, we identified only 1 further death from infection. When we looked at the FDA global safety database after this date, we again observed no further deaths from infection.

In summary, we identified and confirmed that pralsetinib was markedly superior to standard chemotherapy plus or minus immunotherapy in the frontline setting, reinforcing current guidelines that recommend selective RET inhibitors as first-line treatment for RET-positive non-small cell lung cancer. This was underpinned by a strong response rate, durable duration of response, and progression-free survival benefit that was maintained in patients with and without brain metastases.

We did identify a safety signal regarding serious infections, but this was effectively mitigated by increased awareness, prompt management of infection when it occurred, and dose reduction or discontinuation when infection was severe.

Source:

Popat S, Besse B, Calles A, Cecere FLL, Cho BC, Ferrara R, et al. Efficacy and safety of pralsetinib as first-line treatment of RET fusion–positive advanced or metastatic non–small cell lung cancer (NSCLC): The phase 3 AcceleRET-Lung study. Presented at the ASCO Annual Meeting. 2026.