Rigel Pharmaceuticals has issued a warning to healthcare providers regarding an elevated risk of severe and potentially fatal infections in lung cancer patients receiving pralsetinib (Gavreto). This alert follows an ad-hoc analysis of the phase III AcceleRET-Lung trial (NCT04222972), which revealed a significant imbalance in infection rates between the pralsetinib and standard of care (SOC) arms.
The FDA approved pralsetinib in August 2023 for RET fusion-positive non-small cell lung cancer (NSCLC). The AcceleRET-Lung trial included 226 patients with metastatic RET fusion-positive NSCLC, randomized 1:1 to either pralsetinib or SOC. SOC for non-squamous histology was platinum-based therapy with or without pembrolizumab, followed by maintenance therapy. For squamous histology, SOC was platinum/gemcitabine or platinum plus pembrolizumab plus paclitaxel/nab-paclitaxel, followed by maintenance pembrolizumab.
The analysis showed a higher incidence of fatal events in the pralsetinib arm (13%, n=14), with 4.6% (n=5) attributed to fatal infections. In contrast, the SOC group had a 4.8% (n=5) fatal event rate, with no deaths due to infection. Among 108 patients treated with pralsetinib, severe (grade 3-5) infections occurred in 25.9% (n=28), compared to 7.7% (n=8) of the 104 patients receiving SOC. This represents a statistically significant increased risk of severe infection in the pralsetinib arm (risk ratio, 3.33; 95% CI, 1.57-7.06).
Types and Timing of Infections
Half of the severe infections in the pralsetinib group emerged within the first 66 days of treatment, with a significant proportion affecting the lungs. Notably, most severe infections were not associated with pre-existing neutropenia or lymphopenia. Severe opportunistic infections, including pneumocystis jirovecii pneumonia, cytomegalovirus pneumonia, legionella pneumonia, and esophageal candidiasis, were observed in 6.5% (n=7) of pralsetinib-treated patients, but not in the SOC group.
Recommendations for Clinicians
The communication from Rigel Pharmaceuticals emphasizes the importance of vigilant monitoring for infection signs in patients undergoing pralsetinib treatment. Detected infections should be managed according to established local or institutional guidelines. Ensuring patients are current with recommended vaccinations is also advised. The letter recommends withholding pralsetinib during active infections, with potential resumption at a reduced dose after infection resolution, as per prescribing information. Permanent discontinuation is recommended for life-threatening infections.
