Letter Warns Clinicians of Severe Infections With Pralsetinib for NSCLC

The pharmaceutical company behind pralsetinib wrote a letter warning clinicians about severe and fatal infections for patients with lung cancer who are being treated with the drug.

Rigel Pharmaceuticals, the manufacturer of pralsetinib (Gavrelto) wrote a letter to healthcare providers warning about severe and fatal infection risks in patients with lung cancer observed with the drug in an ad-hoc analysis of the phase III AcceleRET-Lung trial (NCT04222972).^1,2

The FDA approved pralsetinib in August 2023 for patients with RET fusion-positive non-small cell lung cancer (NSCLC). The drug was also approved for RET-mutant medullary thyroid cancer. But in July 2023, the drug manufacturer pulled the indication after determining that the phase 3 AcceleRET-MTC trial (NCT04760288) needed to convert the agent’s accelerated approval into a full approval was no longer feasible.³

Pralsetinib Infection Data From AcceleRET-Lung

The AcceleRET-Lung trial included 226 patients with metastatic RET fusion-positive NSCLC. They were randomly assigned 1:1 to receive either pralsetinib or standard of care (SOC). SOC treatment for patients with non-squamous histology was platinum-based therapy with or without pembrolizumab (Keytruda), followed by maintenance platinum therapy with or without pembrolizumab. For patients with squamous histology, SOC was platinum/gemcitabine or platinum plus pembrolizumab plus paclitaxel/nab-paclitaxel followed by maintenance pembrolizumab.

Now, the Dear Health Care Provider letter is stating that an ad-hoc analysis of the trial showed an imbalance of the risk of severe and fatal infection, including severe opportunistic infections, between the pralsetinib and SOC treatment groups. Specifically, 13% (n=14) of patients in the pralsetinib cohort experienced a fatal event, including 4.6% (n=5) who experienced a fatal infection. Conversely, the fatal effect rate was 4.8% (n=5) in the SOC group, with no patients dying of infection.

When the ad-hoc review was conducted, 108 patients were treated with pralsetinib and 104 were treated with SOC. Severe (grade 3-5) infection events occurred in 25.9% (n=28) of patients in the pralsetinib arm, compared with 7.7% (n=8). This demonstrated a statistically significant increased risk of severe infection in the pralsetinib arm (risk ratio, 3.33; 95% CI, 1.57-7.06).

Half of the severe infections in the pralsetinib group occurred within the first 66 days of treatment, with approximately half also occurring in the lungs. Most severe infections did not have neutropenia or lymphopenia precluding them.

Severe opportunistic infections, including pneumocystis jirovecii pneumonia, cytomegalovirus pneumonia, legionella pneumonia and esophageal candidiasis occurred in 7 (6.5%) of pralsetinib-treated patients, and in 0 patients receiving SOC.

“This data supports concluding that severe infections, including opportunistic infections, warrants an update to the Product Information in Warnings and Precautions, to alert prescribers and patients of this risk,” the letter explained.

What to Do If Patients Develop an Infection on Pralsetinib

The letter urged healthcare providers to closely monitor for signs of infection in patients being treated with pralsetinib. If an infection is detected, it should be treated according to local or institutional guidelines. Clinicians should also ensure that patients are up to date on their vaccinations.

Pralsetinib can be withheld in patients experiencing an active infection. When the infection clears, administration of the drug can be resumed with dose reduction, per labeled prescribing information. The drug should be permanently discontinued in patients who experience a life-threatening infection.

References

1. Rigel Pharmaceuticals. Gavreto® (pralsetinib), New Warning and Precaution: Severe and Fatal Infection. Published October 29, 2024. Accessed November 3, 2024. https://gavreto-hcp.com/downloads/pdf/GAVRETO-Dear-Doctor-Letter.pdf

2. A study of pralsetinib versus standard of care for first-line treatment of advanced non-small cell lung cancer (NSCLC) (AcceleRET-Lung). ClinicalTrials.gov. Updated October 8, 2024. Accessed November 4, 2024. https://tinyurl.com/2sd5u3vn

3. Genentech withdraws use of Gavreto in US for a type of thyroid cancer, says partner Blueprint. Reuters. June 30, 2023. Accessed July 5, 2023. https://www.reuters.com/business/healthcare-pharmaceuticals