Selpercatinib Extends PFS in First-line RET-Positive NSCLC

TOPLINE:

The RET kinase inhibitor selpercatinib (Retevmo) more than doubled progression-free survival (PFS) compared with standard chemotherapy with or without pembrolizumab (Keytruda) in the first-line setting among patients with RET fusion advanced/metastatic non-small cell lung cancer (NSCLC). 

METHODOLOGY:

• Approximately 1%–2% of all NSCLC cases carry a RET fusion that stimulates oncogenic activity and promotes unchecked cellular proliferation.

• Selpercatinib is a RET kinase inhibitor approved in the US to treat locally advanced/metastatic RET fusion-positive NSCLC.

• To compare selpercatinib with standard-of-care NSCLC treatment, the LIBRETTO-431 trial randomly assigned 159 patients with RET fusion-positive disease to selpercatinib — 160 mg twice per day — and 102 to cisplatin/carboplatin with pemetrexed.

• Patients were new to systemic therapy, and about 80% of the control group also received pembrolizumab at the investigators’ discretion; 62% of control patients crossed over to selpercatinib at progression.

TAKEAWAY:

• At a median follow-up of approximately 19 months, the selpercatinib arm demonstrated a median PFS of 24.8 months vs 11.2 months in the control arm (hazard ratio [HR], 0.482; P KIF5B RET fusions.

• Among approximately 20% of patients with baseline brain metastases, the intracranial response rate with selpercatinib was 82.4% vs 58.3% in the control group. At 12 months, the rate of new onset brain metastases was 1.1% with selpercatinib vs 14.7% with standard-of-care.

• Overall survival data were not mature in the interim analysis, but the hazard ratio was 0.961, favoring selpercatinib.

• The selpercatinib group had a higher rate of grade 3 or higher adverse events — 70.3% vs 57.1 % in the control group — but also had a much longer median time on treatment — 16.7 months vs 9.8 months in the control arm. The most common adverse events with selpercatinib included increased liver enzymes, hypertension, diarrhea, and edema; myelosuppression was the most common adverse event in the control arm. A total of 7 adverse event–related deaths occurred in the selpercatinib arm (4.4%) and none in the control group.

IN PRACTICE:

“Selpercatinib should be considered a first-line standard of care in RET fusion-positive advanced NSCLC,” the authors write. “These results reinforce the importance of genomic testing to identify RET fusions at the time of diagnosis to inform initial therapy.”

SOURCE:

The study was presented by Herbert Ho Fung Loong, MD of the Chinese University of Hong Kong at the 2023 European Society for Medical Oncology annual meeting; results were also published in the New England Journal of Medicine.

LIMITATIONS:

Overall survival data were immature and confounded by crossover to the selpercatinib group.

DISCLOSURES:

The work was funded by selpercatinib maker Eli Lilly. Investigators had numerous ties to the company, including the presenter, who is an advisor and speaker for Lilly. Several investigators are Lilly employees.

M. Alexander Otto is a physician assistant with a master’s degree in medical science and a journalism degree from Newhouse. He is an award-winning medical journalist who worked for several major news outlets before joining Medscape. Alex is also an MIT Knight Science Journalism fellow. Email: [email protected] .