Eight Infection-Related Deaths in Phase 3 RET Lung Cancer Drug Trial Raise Safety Concerns Despite Efficacy

Eight infection-related deaths were reported in a phase 3 study of pralsetinib, a treatment for RET fusion-positive non-small cell lung cancer. Although the drug demonstrated efficacy, the findings raised safety concerns.

On the 17th, BioOn introduced results from the global phase 3 AcceleRET-Lung study evaluating pralsetinib as first-line treatment. The findings were first presented at the 2026 American Society of Clinical Oncology (ASCO) Annual Meeting.

The study was conducted in 74 institutions across 22 countries and enrolled 223 patients with RET fusion-positive advanced non-small cell lung cancer. Patients were assigned to receive pralsetinib 400㎎ or platinum-based standard therapy.

Pralsetinib demonstrated an efficacy advantage. Median progression-free survival was 18.7 months in the pralsetinib group and 9.0 months in the standard-therapy group. The risk of disease progression or death was reduced by 41%.

The objective response rate was higher with pralsetinib, at 65.5% versus 41.6% with standard therapy, and median duration of response was also longer, at 20.6 months versus 9.7 months.

However, infection signals were prominent in the safety data. The overall infection rate was 71.3% in the pralsetinib group, compared with 51.9% in the standard-therapy group. Pneumonia occurred in 19.4% versus 5.8%, and urinary tract infections in 17.6% versus 7.7%.

Opportunistic infections occurred in 9.3% of patients in the pralsetinib group, more than nine times the 1.0% rate in the standard-therapy group. Eight infection-related deaths (7.4%) occurred only in the pralsetinib group. The researchers therefore noted that infection monitoring should be intensified during treatment.

This infection signal was not observed for the first time in this study. In a 2021 report on pralsetinib use in South Korea, extrapulmonary tuberculosis developed in two of 10 patients.

Chinese researchers reported identifying opportunistic pathogens, including herpesviruses and Pneumocystis, in all eight patients who developed pneumonia during pralsetinib treatment. The median time to pneumonia onset was approximately 2.15 months after treatment initiation.

Neutropenia resulting from bone marrow suppression was initially cited as a possible cause of the infections. Among grade 3 or higher treatment-related adverse events in the pralsetinib group, neutropenia occurred in 10.2% of patients, and decreased neutrophil counts occurred in 7.4%.

However, because platinum-based chemotherapy can also cause bone marrow suppression in the standard-therapy group, the researchers analyzed that neutropenia alone could not explain the difference in infections.

Accordingly, the possibility of off-target JAK1/2 inhibition by pralsetinib was proposed as an alternative hypothesis. The JAK/STAT pathway is involved in antiviral and antifungal immunity, and inhibition of this pathway could increase the risk of opportunistic infections.

In a case report published in 2024, a patient receiving pralsetinib experienced five severe infections, including two episodes of pneumonia, two spinal disk infections and one Pneumocystis infection. The author suggested that potential off-target JAK1/2 activity may have contributed to the opportunistic infections.

However, the researchers emphasized that off-target JAK1/2 inhibition has not yet been fully validated clinically. They explained that although an infection signal was identified, additional research is needed to determine its cause.

The ASCO living guideline highlighted serious and fatal infections in the pralsetinib group even before the formal results were released. The guideline stated that, in its clinical interpretation, the study sponsor had been required to communicate the safety warning to health authorities.

BioOn reported that the study reaffirmed pralsetinib’s value as a first-line treatment while also showing that, in an era of longer survival, safety has emerged as a key factor in treatment selection.