Pralsetinib Approved in Europe for RET Fusion+ Advanced NSCLC

The European Commission has granted a conditional marketing authorization to pralsetinib for use as a single agent in adult patient with RET fusion–positive advanced non–small cell lung cancer who did not previously receive a RET inhibitor.

The European Commission has granted a conditional marketing authorization to pralsetinib (Gavreto) for use as a single agent in adult patient with RET fusion–positive advanced non–small cell lung cancer (NSCLC) who did not previously receive a RET inhibitor.1

The regulatory decision was supported by data from the ongoing phase 1/2 ARROW trial (NCT03037385), which showed that pralsetinib produced durable responses in this patient population.

Specifically, in 75 treatment-naïve patients, pralsetinib elicited an overall response rate (ORR) of 72.0% (95% CI, 60.4%-81.8%) and the median duration of response (DOR) had not yet been reached (95% CI, 9.0–not reached [NR]). In 136 patients who previously received platinum-based chemotherapy, the agent elicited an ORR of 58.8% (95% CI, 50.1%-67.2%), with a median DOR of 22.3 months (95% CI, 15.1–NR).

“Today’s approval represents an important step forward in delivering precision medicine to people with RET fusion–positive advanced NSCLC, for whom treatment options have historically been limited,” Levi Garraway, MD, PhD, chief medical officer and head of Global Product Development at Roche, stated in a press release. “By using cancer genomic profiling up front, healthcare professionals may identify specific genetic alterations that predict clinical benefit of targeted treatment options like [pralsetinib] in the first-line setting.”

The multicohort, open-label, phase 1/2 ARROW study, enrolled patients with locally advanced or metastatic solid tumors and a pathologically or genetically documented RET fusion or mutation. Patients needed to be at least 18 years of age.2 Those enrolled to the NSCLC subgroup needed to have locally advanced or metastatic disease, documented RET fusion.

Patients also needed to have measurable disease at baseline and an ECOG performance status of 0 to 2. Those with untreated central nervous system metastases were allowed if it was not linked with progressive neurological symptoms.

In the dose-escalation portion of the study, participants were given a daily dose of oral pralsetinib ranging from 30 mg to 600 mg. In the phase 2 expansion portion of the research, patients received the RET inhibitor at the recommended phase 2 dose (RP2D) of 400 mg, administered once daily. Treatment was delivered until progressive disease, unacceptable toxicity, withdrawn consent, or investigator decision.

Treatment after progression was permitted per investigator decision. Dose reductions for pralsetinib-related toxicities were also allowed. Treatment was discontinued if a reduction below 100 mg was needed. Doses could be interrupted for treatment-related adverse effects (TRAEs) for up to 28 days.

The primary end point of the phase 1 portion of the trial was to identify the maximum tolerated dose and the RP2D of pralsetinib, as well as to evaluate the safety of the agent. Secondary end points included ORR, as well as examining the pharmacokinetics and pharmacodynamics of the agent.

At a data cutoff date of May 22, 2020, 587 patients were screened and 521 were enrolled and received treatment. Of those who were treated, 471 received pralsetinib at the RP2D of 400 mg once daily across the dose-escalation and -expansion portions of the research. Of these patients, 223 had RET fusion–positive NSCLC, 162 had medullary thyroid cancer, and 76 had other cancers. Moreover, of those with RET fusion–positive NSCLC, 87 had previously received platinum-based chemotherapy and 27 were naïve to systemic treatment.

Additional data from the trial published in the Lancet Oncology showed that in the 87 patients who had prior platinum-based therapy, the disease control rate (DCR) was 91% (95% CI, 83%-96%). The 6- and 12-month ORRs in this subset were 83% (95% CI, 73%-94%) and 74% (95% CI, 61%-87%), respectively. The clinical benefit rate (CBR) in this group was 69% (95% CI, 58%-79%).

In the 27 patients who did not receive prior systemic treatment, the DCR was 85% (95% CI, 66%-96%) and the CBR was 70% (95% CI, 50%-86%). The ORR at 6 months in this subset was 74% (95% CI, 52%-96%); at 12 months, this rate was 26% (95% CI, 0%-52%).

The mean treatment duration in the NSCLC safety population (n = 233) was 8.1 months. Ninety-three percent of patients experienced TRAEs, 48% of which were grade 3 or higher in severity. The most common grade 3 or higher toxicities were neutropenia (18%), hypertension (11%), and anemia (10%). Serious TRAEs were experienced by 24% of patients, and most frequently included pneumonia (4%), pneumonitis (4%), anemia (2%), and neutropenia (2%).

Thirty-eight percent of patients required dose reductions because of TRAEs and 6% of patients discontinued treatment because of these effects. No deaths determined to be related to the RET inhibitor were reported, although 17% of patients died by the data cutoff.

In September 2020, the FDA approved pralsetinib for the treatment of adult patients with metastatic RET fusion–positive NSCLC, as detected by an FDA-approved test.3 The decision was based on earlier data from ARROW.


  1. European Commission approves Roche’s Gavreto (pralsetinib) for the treatment of adults with RET fusion-positive advanced non-small cell lung cancer. News release. Roche; November 19, 2021. Accessed November 19, 2021.
  2. Gainor JF, Curigliano G, Kim D-W, et al. Pralsetinib for RET fusion-positive non-small-cell lung cancer (ARROW): a multi-cohort, open-label, phase 1/2 study. Lancet Oncol. 2021;22(7):959-969. doi:10.1016/S1470-2045(21)00247-3
  3. Genentech announces FDA approval of Gavreto (pralsetinib) for the treatment of adults with metastatic RET fusion-positive non-small cell lung cancer. News release. Genentech. September 4, 2020. Accessed November 19, 2021.