Pralsetinib in RET-Positive Lung Cancer: Doubled PFS in the First Line
In this article
First-Line PFS Advantage Over Chemotherapy, but the Infection Signal Requires Attention
First-Line Treatment in Rare Driver Mutations Now Depends on Molecular Testing
Identifying driver alterations such as EGFR, ALK, ROS1, BRAF, MET, NTRK, HER2, and RET in lung cancer has fundamentally changed treatment decisions in metastatic disease. RET fusions are rare, but they can be targeted with selective RET inhibitors. Comprehensive molecular testing at diagnosis in advanced nonsquamous NSCLC is therefore no longer a luxury: it is a fundamental requirement for accessing the right treatment.
The efficacy of chemotherapy-immunotherapy standards in patients with RET fusions may be limited, and the contribution of immunotherapy is not always at the expected level. By contrast, agents such as pralsetinib and selpercatinib that directly target the RET driver may provide high response rates and prolonged disease control in this patient group. AcceleRET-Lung is the pivotal study in which pralsetinib tested this rationale in the first line at the randomized phase 3 level.
Brief Concept Note: What Is a RET Fusion?
A RET fusionoccurs when the RET gene joins another gene, creating a continuously active growth signal in the cancer cell. This alteration may become the main driver of the cancer. When a RET fusion is detected, the signal can be targeted with selective RET inhibitors such as pralsetinib or selpercatinib.
How Does Pralsetinib Work?
Pralsetinib is an oral, potent, selective RET tyrosine kinase inhibitor. It aims to suppress the abnormal growth signal generated by a RET fusion inside the cell. Rather than broadly targeting all rapidly dividing cells, as chemotherapy does, it therefore targets the tumor’s molecular driver.
Pralsetinib had previously received approval in RET fusion-positive metastatic NSCLC based on ARROW study data. AcceleRET-Lung investigated whether using the drug in the first line, before a patient had received systemic treatment for metastatic disease, was better than standard treatment.
Brief Concept Note: What Is a Tyrosine Kinase Inhibitor?
A tyrosine kinase inhibitoris a class of targeted drug that inhibits enzymes transmitting growth and survival signals in cancer cells. For these drugs to work, the driver alteration targeted in the tumor must be demonstrated using appropriate molecular tests.
Pralsetinib Was Tested Against Platinum-Based Standard Treatment
AcceleRET-Lung is an open-label, randomized phase 3 study in RET fusion-positive advanced or metastatic NSCLC. It included patients who had not previously received systemic treatment for metastatic disease and had an ECOG performance status of 0–1. Patients with stable brain metastases were also allowed.
Patients were randomized in a 1:1 ratio to pralsetinib or standard treatment. The standard treatment arm received platinum-based chemotherapy, with pembrolizumab added in eligible patients. The primary endpoint was investigator-assessed progression-free survival.
| Aspect | Pralsetinib arm | Standard treatment arm | Clinical significance |
|---|---|---|---|
| Treatment | Oral selective RET inhibitor pralsetinib | Platinum-based chemotherapy; pembrolizumab could be added in eligible patients | Targeted treatment was compared with the chemotherapy ± immunotherapy standard. |
| Patient group | RET fusion-positive advanced/metastatic NSCLC; patients with no prior systemic treatment for metastatic disease | The patient population defining the first-line treatment standard. | |
| Brain metastases | Patients with stable brain metastases were allowed | CNS control is an important clinical issue in RET-positive disease. | |
| Primary endpoint | Investigator-assessed progression-free survival | The period during which the disease remained controlled without progression was assessed. | |
| Crossover | Not applicable | Switching to pralsetinib after progression was allowed | May complicate interpretation of the overall survival difference. |
Brief Concept Note: What Are Randomized Phase 3, PFS, and Crossover?
A randomized phase 3 studyis the research stage in which a new treatment is compared with standard treatment in a large patient group and has the potential to change clinical practice. PFSmeans progression-free survival: the time during which the disease remains controlled without progression or death. Crossoverallows a patient in the control arm to switch to experimental treatment after disease progression; this may be valuable ethically but can reduce the overall survival difference.
Median PFS: 18,7 Months vs 9,0 Months
In AcceleRET-Lung, pralsetinib significantly prolonged progression-free survival compared with standard treatment. Median PFS was 18,7 monthsin the pralsetinib arm and 9,0 months in the standard treatment arm. HR was reported as 0,59 and the P value as .0027 .
This result indicates an approximately 41% relative reduction in the risk of progression or death with pralsetinib. In a rare and molecularly defined subgroup such as RET fusion-positive disease, it supports the strong clinical value of targeted treatment in the first line.
Response Rate and Duration of Response Also Favor Pralsetinib
Pralsetinib did not merely delay disease progression; it also produced better tumor responses than standard treatment. The objective response rate was %65,5in the pralsetinib arm and %41,6 in the standard treatment arm. This approximately 24-percentage-point absolute differencedemonstrates the tumor-shrinking capacity of targeted treatment.
Duration of response also favored pralsetinib. The median duration of response was 20,6 monthsin the pralsetinib arm and 9,7 months in the standard treatment arm. Responses with pralsetinib were therefore not only more frequent but also more durable.
Brief Concept Note: What Are ORR and Duration of Response?
ORRmeans objective response rate: the proportion of patients whose tumors shrink measurably. Duration of responsedescribes how long this tumor shrinkage lasts. A high ORR means rapid tumor control, while a long duration of response means more durable disease control.
| Outcome | Pralsetinib | Standard treatment | Effect measure | Clinical interpretation |
|---|---|---|---|---|
| Median PFS | 18,7 months | 9,0 months | HR 0,59; P=.0027 | Pralsetinib significantly delayed disease progression. |
| Objective response rate | %65,5 | %41,6 | Approximately 24-point absolute difference | Tumor shrinkage was more frequent with pralsetinib. |
| Median duration of response | 20,6 months | 9,7 months | Approximately more than twice as long | Responses were more durable with pralsetinib. |
| Overall survival | No significant difference reported | The crossover effect is important | Switching from the control arm to pralsetinib may reduce the OS difference. | |
Why Has the OS Difference Not Been Established?
No significant difference between the two arms was reported in the overall survival analysis. However, the crossover design must be considered when interpreting this result. Some patients in the standard treatment arm were able to switch to pralsetinib after progression. This increases the opportunity for control-arm patients to receive effective targeted treatment and may statistically reduce the OS difference between the arms.
The strongest message of AcceleRET-Lung today therefore concerns PFS, ORR, and duration of response. The lack of a significant OS result does not negate the clinical value of pralsetinib in the first line, but it requires a balanced explanation of survival data and the crossover effect in treatment decisions.
Truecheck Note: OS Neutral, PFS Positive
In this study, pralsetinib showed clear superiority in PFS, response rate, and duration of response. The absence of a reported significant difference in overall survival requires careful interpretation, particularly because switching from standard treatment to pralsetinib was allowed. This finding does not mean that treatment is ineffective; rather, it shows that treatment sequencing complicates the OS analysis.
Efficacy Is Strong, but Infection Risk Must Be Central to Treatment Monitoring
Although the efficacy data for pralsetinib are strong, infection risk was particularly notable in the AcceleRET-Lung safety analysis. In the pralsetinib arm, the reported rate of any-grade infection was %71,3and that of grade 3 or higher infection was %28,7 . In the standard treatment arm, these rates were %51,9 and %9,6 , respectively.
Fatal infections occurred in the pralsetinib arm. The study protocol was therefore updated in October 2024 regarding infection monitoring and dose management. This finding shows that pralsetinib should not be viewed as an “easy and risk-free targeted treatment.” It may be very effective in the right patient, but close follow-up, early warning for infections, and treatment interruptions/dose reductions when necessary are critical.
Brief Concept Note: What Are Grade 3 Infection and Fatal Infection?
Grade 3 infectionmeans a severe infection; intravenous antibiotics, hospitalization, or treatment interruption may be needed. Fatal infectionmeans an infection resulting in loss of life. Fever, cough, shortness of breath, urinary tract symptoms, and deterioration in general condition therefore require prompt assessment during pralsetinib treatment.
Practical Monitoring Note
- Baseline assessment: History of infection, lung disease, immunosuppression, steroid use, and comorbidities should be assessed.
- Patient education: The patient should seek care immediately for fever, chills, cough, shortness of breath, urinary symptoms, or sudden weakness.
- Laboratory and clinical follow-up: Complete blood counts, signs of inflammation, and clinical examination should be monitored regularly.
- Dose management: Decisions to interrupt treatment, reduce the dose, or discontinue treatment in severe infection should not be delayed.
- Opportunistic infections: Opportunistic infections such as Pneumocystis jirovecii and fungal infections should be kept in mind.
From Chemotherapy to Selective RET Inhibitors in RET Fusion-Positive NSCLC
Early treatment of RET fusion-positive NSCLC largely followed general NSCLC algorithms. Platinum-pemetrexed chemotherapy was used, sometimes with the addition of immunotherapy. However, immunotherapy efficacy in driver mutation-positive NSCLC may often be more limited, and targeted treatments may provide higher response rates.
Selective RET inhibitors such as pralsetinib and selpercatinib changed treatment in RET fusion-positive NSCLC. ARROW established the basis for approval by showing that pralsetinib could produce strong, durable responses. LIBRETTO-431 had shown that selpercatinib significantly prolonged PFS over chemotherapy ± pembrolizumab in the first line. AcceleRET-Lung is a similar first-line validation step for pralsetinib.
| Approach / study | Treatment | Patient context | Key message | Clinical interpretation |
|---|---|---|---|---|
| Conventional standard treatment | Platinum-pemetrexed ± pembrolizumab | Advanced NSCLC with an unknown RET fusion status or no access to targeted treatment | Provides a systemic treatment option but does not directly target the RET driver. | Becomes less prominent as a first choice as molecularly targeted treatments become available. |
| ARROW | Pralsetinib | Treatment-naive and previously treated RET fusion-positive NSCLC | Pralsetinib provided strong, durable responses. | The single-arm dataset forming the basis for pralsetinib approval. |
| LIBRETTO-431 | Selpercatinib | First-line RET fusion-positive advanced NSCLC | Selpercatinib significantly prolonged PFS over chemotherapy ± pembrolizumab. | Demonstrated the strong value of RET-targeted treatment in the first line. |
| AcceleRET-Lung | Pralsetinib | First-line RET fusion-positive advanced/metastatic NSCLC | PFS 18,7 vs 9,0 months; ORR 65,5% vs 41,6%. | Randomized phase 3 data supporting first-line use of pralsetinib. |
This Table Is Not a Direct Comparison Between Drugs
Selpercatinib and pralsetinib were evaluated in different studies with different designs and patient distributions. The question “Which is better?” therefore cannot be answered by this table. The correct message is that the approach of using a selective RET inhibitor in the first line for RET fusion-positive NSCLC is supported by increasingly strong evidence.
The Right Treatment Cannot Be Selected Without Comprehensive Molecular Testing at Diagnosis
The most practical message of AcceleRET-Lung is that RET fusions should be identified at diagnosis. If a patient starts chemotherapy-immunotherapy first and a RET fusion is identified later, the opportunity for targeted treatment in the first line may be missed. Comprehensive NGS-based molecular testing in advanced nonsquamous NSCLC should therefore be completed before treatment whenever possible.
Pralsetinib may be a strong option in the right patient, but patient selection and follow-up are very important because of infection risk. The benefit-risk balance should be carefully assessed, particularly in patients with older age, chronic lung disease, frequent previous infections, immunosuppression, steroid use, poor performance status, or serious comorbidities.
Brief Concept Note: Why Is NGS Important?
NGSmeans next-generation sequencing and can identify many targetable genetic alterations simultaneously. Because RET fusions are rare, they can easily be missed with limited testing alone. In advanced NSCLC, NGS is a fundamental tool for selecting the right targeted treatment.
Issues to Consider in Patient Selection
- The RET fusion should be confirmed: The treatment decision should be supported by FDA-approved or reliable validated NGS/FISH/similar tests.
- Brain metastasis status should be known: Patients with stable brain metastases could be enrolled; details of CNS efficacy are important for clinical decisions.
- Infection risk should be assessed: Previous serious infections, immunosuppression, and chronic lung disease should be assessed.
- Blood pressure and liver tests should be monitored: Pralsetinib also requires monitoring for hypertension and hepatotoxicity.
- Crossover information should be explained: The absence of a clear OS difference may be related to patients in the control arm subsequently receiving pralsetinib.
How Should This Be Discussed With the Patient?
“If your lung cancer has a specific genetic alteration called a RET fusion, oral targeted drugs directed at this alteration can be used. In a new phase 3 study, pralsetinib controlled the disease longer and produced more tumor shrinkage than chemotherapy. However, the risk of serious infection with this drug was notable. Before starting treatment, your infection risk, general condition, and access to close follow-up should therefore be assessed together.”
RET-Targeted Treatment Gains Strength in the First Line, but Safety Management Must Remain Central
Academic Assessment
AcceleRET-Lung is an important ASCO 2026 result showing that first-line pralsetinib may provide longer disease control and higher response than chemotherapy in RET fusion-positive lung cancer.
The study once again demonstrates the value of molecular testing at diagnosis for rare driver mutations and of early targeted treatment in the appropriate patient.
However, infection risk requires using this treatment in the right patient with careful monitoring and toxicity management at the center of care.
How Will the First-Line Role of Pralsetinib Be Examined?
AcceleRET-Lung shows that pralsetinib provides a strong first-line PFS and response advantage, but several critical questions remain on the clinical agenda. Most importantly, how will infection risk be managed in real-world practice, and in which patients will pralsetinib be the safest option?
Open Questions
- How will infection risk be predicted? Which clinical or laboratory parameters can identify the risk of serious infection?
- Clinical positioning relative to selpercatinib: How should the choice between two selective RET inhibitors be made for each patient?
- CNS efficacy: What is the long-term intracranial control with pralsetinib in patients with brain metastases?
- OS maturity: Will a long-term overall survival difference emerge despite the crossover effect?
- Real-world data: Will the balance of efficacy and safety be maintained in patients who are older, have comorbidities, or have a high infection risk?
- Resistance mechanisms: Which RET resistance mutations or bypass pathways develop after pralsetinib?
Truecheck Note
Pralsetinib is an approved RET inhibitor for RET fusion-positive metastatic NSCLC, and AcceleRET-Lung has shown a randomized first-line PFS advantage. However, the serious/fatal infection warning is central to treatment decisions. It should therefore not be interpreted as “risk-free because it is targeted treatment.”
Pralsetinib Strengthens First-Line Targeted Treatment in RET Fusion-Positive NSCLC
The AcceleRET-Lung phase 3 study presented at ASCO 2026 showed that pralsetinib provided a significant first-line PFS advantage over standard treatment in RET fusion-positive advanced or metastatic NSCLC. Median PFS was reported as 18,7 versus 9,0 months, HR 0,59, and P=.0027. The objective response rate was 65,5% versus 41,6%, and median duration of response was 20,6 versus 9,7 months.
These results show a shift in RET fusion-positive patients from the general chemotherapy-immunotherapy algorithm toward a molecularly targeted first-line approach. However, the lack of a clear overall survival difference and the crossover effect require balanced interpretation of the results.
The most important safety message concerns infection risk. The occurrence of high-grade and fatal infections in the pralsetinib arm shows that this treatment should be administered in experienced centers with close follow-up and patient education. While AcceleRET-Lung demonstrates the strength of RET-targeted treatment, it also reminds us that toxicity management is an integral part of treatment success even with targeted drugs.
Sources
- ASCO 2026 Abstract 8504. Efficacy and safety of pralsetinib as first-line treatment of RET fusion-positive advanced or metastatic NSCLC: The phase 3 AcceleRET-Lung study.
- Rigel Pharmaceuticals. Oral presentation at ASCO Annual Meeting to feature final data from the Phase 3 AcceleRET-Lung clinical trial of pralsetinib. 21 May 2026.
- ClinicalTrials.gov. A Study of Pralsetinib Versus Standard of Care for First-Line Treatment of RET Fusion-Positive Metastatic NSCLC. NCT04222972.
- U.S. FDA. FDA approves pralsetinib for non-small cell lung cancer with RET gene fusions. 9 August 2023.
- The ASCO Post. Final Report on Pralsetinib in Advanced RET Fusion-Positive NSCLC. 9 April 2026.
- Besse B et al. Final efficacy and safety data from the phase I/II ARROW trial of pralsetinib in patients with advanced RET fusion-positive NSCLC. Journal of Clinical Oncology. 2026.
- LIBRETTO-431 Trial Investigators. First-Line Selpercatinib or Chemotherapy and Pembrolizumab in RET Fusion-Positive NSCLC. New England Journal of Medicine. 2023.
- Oncology Nursing News. Letter Warns Clinicians of Severe Infections With Pralsetinib for NSCLC. 2024.
- GAVRETO prescribing information. Serious infections, including opportunistic infections boxed warning.
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