Selpercatinib delivers superior outcomes, may ‘reduce the burden of NSCLC’
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Key takeaways:
- Selpercatinib conferred a markedly higher objective response rate compared with control treatment.
- Treatment-related adverse events occurred more frequently among those treated with selpercatinib.
Treatment with selpercatinib for advanced RET fusion-positive non-small cell lung cancer resulted in significantly longer PFS compared with platinum-based chemotherapy with or without pembrolizumab, study results showed.
The findings — published in The New England Journal of Medicine — reinforce the need for genomic testing for RET fusions upon diagnosis, according to researchers.
“Although treatment for advanced or metastatic NSCLC has improved in recent years, it has been reported that more than 40% of patients do not receive therapy after first-line treatment, which indicates the need for the most effective therapies to be used early in treatment,” Caicun Zhou, MD, PhD, professor at Tongji University School of Medicine's Shanghai Pulmonary Hospital, and researchers wrote. “In this randomized trial of a targeted agent in comparison with a PD-1 inhibitor plus chemotherapy .... the efficacy of selpercatinib was superior in patients with RET fusion–positive NSCLC.”
Background and methodology
The RET inhibitor selpercatinib (Retevmo, Eli Lilly & Co.) showed efficacy among patients with advanced RET fusion-positive NSCLC in a prior nonrandomized phase 1/phase 2 study.
Researchers conducted a randomized phase 3 study to assess the efficacy and safety of first-line therapy with selpercatinib compared with a control treatment of platinum-based chemotherapy with or without pembrolizumab (Keytruda, Merck) among adults with advanced RET fusion-positive NSCLC.
Investigators randomly assigned 212 patients in the intent-to-treat-pembrolizumab population to receive either selpercatinib (n = 129) or chemotherapy plus pembrolizumab (n = 83).
PFS assessed by blinded independent central review in both the intent-to-treat-pembrolizumab population and the overall intent-to-treat population served as the study’s primary endpoint.
Researchers allowed for crossover from the control group to the investigative arm if disease progression occurred while receiving control treatment.
Results, next steps
At a median follow-up of 19 months, a preplanned interim efficacy analysis showed median PFS of 24.8 months (95% CI, 16.9 to not estimable) with selpercatinib and 11.2 months (95% CI, 8.8–16.8) with control treatment (HR = 0.46; 95% CI, 0.31–0.7).
Objective responses to therapy occurred in 84% (95% CI, 76–90) of patients in the selpercatinib group compared with 65% (95% CI, 54–75) among those who received control treatment.
Researchers noted a cause-specific HR for time to disease progression affecting the central nervous system of 0.28 (95% CI, 0.12–0.68).
Efficacy results in the overall intent-to-treat population (n = 261) appeared similar to those in the intent-to-treat-pembrolizumab population, with adverse events occurring in both groups at rates consistent with previous reports.
Patients treated with selpercatinib experienced more frequent treatment-related adverse events, including elevated liver function values. Moreover, researchers reported seven patient deaths in the selpercatinib group during or immediately after the study’s treatment period compared with none in the control group.
In an accompanying editorial, Lois Mulligan, PhD, pathology and molecular medicine professor at Queen’s University in Canada, discussed selective RET kinase inhibitors, treatment options for NSCLC and the study findings.
“The effect of selpercatinib on NSCLC with a driver RET fusion event suggests that it may have benefits in other cancers associated with RET alterations,” Mulligan wrote.
“The next generation of RET-selective inhibitors are also in early-phase trials and show promise in overcoming solvent front variants,” she added. “Zhou et al. found that selpercatinib provides a significant improvement on a current standard therapy for patients with RET alterations — an improvement that may yield better survival outcomes and reduce the burden of NSCLC.”
References:
- Mulligan L, et al. N Engl J Med. 2023;doi:10.1056.NEJMe2311295.
- Zhou C, et al. N Engl J Med. 2023;doi:10.1056.NEJMoa2309457.
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