Letter from Rigel Points to New Safety Signal of Pralsetinib in RET+ NSCLC

According to the letter, corresponding product labeling updates will be forthcoming. Providers are recommended to monitor patients closely for signs of infection and properly manage symptoms based on local or institutional guidelines.

A new warning and precaution have been issued for the risk of severe and fatal infection when administering pralsetinib (Gavreto) to patients with metastatic non–small cell lung cancer (NSCLC) harboring a RET fusion, according to a Dear Health Care Provider (DHCP) letter published by the developer, Rigel Pharmaceuticals, Inc.¹

An ad hoc analysis of findings from the ongoing phase 3 AcceleRET-Lung trial (NCT04222972) indicated an imbalance in the risk of severe and fatal infections—which included severe opportunistic infections—between the pralsetinib and comparator therapy arms. Overall, 13.0% (n = 14) of patients in the pralsetinib arm experienced a fatal adverse effect (AE) compared with 4.8% (n = 5) of those who were assigned to receive standard-of-care (SOC) therapy. Fatal infections affected 4.6% (n = 5) of those who received pralsetinib, and none occurred in the SOC arm.

Among 212 patients who received any study treatment in the pralsetinib (n = 108) and SOC arms (n = 104), grade 3 to 5 infections occurred in 25.9% (n = 28) and 7.7% (n = 8) of patients, respectively. Statistical analyses highlighted that the risk of severe infection was significantly higher in the pralsetinib arm (risk ratio, 3.33; 95% CI, 1.57-7.06; P = .0004). Severe opportunistic infections—which may consist of pneumocystis jirovecii pneumonia, cytomegalovirus pneumonia, legionella pneumonia, and esophageal candidiasis—were reported in 6.5% (n = 7) of those who received pralsetinib and none of those who were in the SOC arm.

According to the letter, corresponding product labeling updates will be forthcoming. Providers are recommended to monitor patients closely for signs of infection and properly manage symptoms based on local or institutional guidelines.

Treatment with pralsetinib is currently indicated for adults with metastatic RET fusion-positive NSCLC as detected via an FDA-approved test as well as patients 12 years and older with advanced or metastatic, RET fusion-positive, radioactive iodine-refractory thyroid cancer who require systemic therapy.² The thyroid cancer indication is currently available under accelerated approval status; continued approval for the agent in this population may be dependent on data from a confirmatory trial.

In the international, open-label, phase 3 AcceleRET-Lung trial, patients were randomly assigned to receive pralsetinib or SOC therapy consisting of platinum-containing chemotherapy with or without pembrolizumab (Keytruda).³ Patients with nonsquamous disease were eligible to receive carboplatin or cisplatin plus pemetrexed with optional pemetrexed maintenance or pembrolizumab/carboplatin or cisplatin/pemetrexed followed by pembrolizumab plus optional pemetrexed. Those with squamous histology were candidates to receive carboplatin or cisplatin plus gemcitabine or carboplatin plus paclitaxel/nab-paclitaxel and pembrolizumab.

The trial’s primary end point is progression-free survival. Secondary end points include overall survival, overall response rate, duration of response, clinical benefit rate, disease control rate, changes in ECOG performance status, and safety.

Patients 18 years and older with pathologically confirmed locally advanced or metastatic NSCLC who have not received prior systemic anticancer therapy for metastatic disease are eligible for enrollment on the trial. Other requirements for study entry include having a documented RET fusion, measurable disease per RECIST v1.1 guidelines, and an ECOG performance status of 0 or 1.

Those with tumors that express any other known primary driver alterations apart from RET such as EGFR, ALK, ROS1, MET, and BRAF mutations are ineligible for enrollment on the trial. Patients are also unable to enroll if they have a history of pneumonitis within 12 months of entry, central nervous system (CNS) metastases, or a primary CNS tumor associated with progressive neurological symptoms.

References

1. Important drug warning: Gavreto® (pralsetinib), new warning and precaution: severe and fatal infection. Rigel Pharmaceuticals, Inc. October 24, 2024. Accessed October 29, 2024. https://tinyurl.com/mpnd78a7
2. Rigel Pharmaceuticals issues Dear Healthcare Provider Letter for GAVRETO® (pralsetinib). News release. Rigel Pharmaceuticals, Inc. October 24, 2024. Accessed October 29, 2024. https://tinyurl.com/mpnd78a7
3. 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 October 29, 2024. https://tinyurl.com/2sd5u3vn