Selpercatinib Demonstrates Durable Responses in RET Fusion–Positive NSCLC

In patients who were pretreated and treatment naïve with RET fusion-positive NSCLC, selpercatinib yielded an ORR of 61.5% and 82.6%, respectively.

Selpercatinib elicited durable responses and positive intracranial activity in the treatment of patients with RET fusion–positive non–small cell lung cancer (NSCLC), according to data from the phase 1/2 LIBRETTO-001 trial (NCT03157128) published in The Journal of Clinical Oncology.¹

In patients who received prior platinum-based chemotherapy or were treatment naïve, the overall response rates (ORRs) were 61.5% (95% CI, 55.2%-67.6%) and 82.6% (95% CI, 71.6%-90.7%); 8.1% and 7.2%, respectively, achieved a complete response (CR), 53.4% and 75.4% achieved a partial response (PR), 32.4% and 10.1% had stable disease, and 2.8% and 4.3% had progressive disease.

The median time to response was 1.9 months (range, 0.7-44.2) in the pretreated arm and 1.8 months (range, 0.7-10.8) in the treatment-naïve arm. The median duration of response (DOR) was 31.6 months (95% CI, 20.4-42.3) and 20.3 months (95% CI, 15.4-29.5); the 1-year DOR rates were 73.0% (95% CI, 65.0%-79.5%) and 66.7% (95% CI, 52.4%-77.6%), the 2-year DOR rates were 55.1% (95% CI, 46.4%-62.9%) and 38.1% (95% CI, 24.5%-51.6%), and the 3-year DOR rates were 44.7% (95% CI, 35.7%-53.4%) and 35.4% (95% CI, 22.0%-49.0%).

The median progression-free survival (PFS) was 26.2 months (95% CI, 19.3-35.7) in the pretreated arm and 22.0 months (95% CI, 16.5-24.9). The 1-year PFS rate was 70.6% (95% CI, 64.2%-76.1%) and 70.8% (95% CI, 58.0%-80.3%), the 2-year PFS rate was 52.3% (95% CI, 45.4%-58.7%) and 44.9% (95% CI, 31.8%-57.3%), and the 3-year PFS rate was 41.1% (95% CI, 34.2%-47.9%) and 34.6% (95% CI, 22.3%-47.3%).

The median overall survival (OS) was 47.6 months (95% CI, 35.9-not evaluable [NE]) in the pretreated arm and NE (95% CI, 37.8-NE) in the treatment-naïve arm. The 1-year OS rate was 87.9% (95% CI, 83.1%-91.5%) and 94.1% (95% CI, 85.1%-97.8%), the 2-year OS rate was 67.9% (95% CI, 61.5%-73.5%) and 74.3% (95% CI, 61.9%-83.1%), and the 3-year OS rate was 56.6% (95% CI, 49.8%-62.8%) and 65.6% (95% CI, 52.4%-75.9%).

“[S]elpercatinib showed substantial and durable antitumor activity in patients who received selpercatinib as first-line therapy, in those who had received previous platinum-based chemotherapy, and in those with central nervous system [CNS] metastases at baseline,” senior study author Alexander Drilon, MD, a thoracic medical oncologist and early drug development specialist at Memorial Sloan Kettering Cancer Center, and fellow study authors wrote in the study.¹ “These results reinforce the importance of testing for RET fusions in NSCLC to identify patients who may benefit from first-line selpercatinib treatment.”

The trial enrolled a total of 837 patients, 356 of whom were included in the efficacy population; 247 patients received prior platinum-based chemotherapy treatment, and 69 patients were treatment naïve. All patients received selpercatinib at doses ranging from 20 mg once daily to 240 mg twice daily during phase 1 in continuous 28-day cycles. The recommended dose in phase 2 was 160 mg twice daily.

Eligible patients had RET fusion–positive, locally advanced or metastatic NSCLC. Additional eligibility criteria included an intolerance to or having progressed on standard therapy; measurable or non-measurable disease per RECIST v1.1 guidelines; an ECOG performance status from 0 to 2; a life expectancy of at least 3 months; and adequate hematologic, hepatic, and renal function.²

Exclusion criteria included a symptomatic primary CNS tumor, metastases, untreated spinal cord compression, and leptomeningeal carcinomatosis.

The primary trial end point was ORR assessed by an independent review committee. Secondary end points were DOR, PFS, and OS across all patients and ORR, PFS, and DOR in patients with CNS metastases.

Among patients with measurable CNS metastases at baseline (n = 26), ORR was 85% (95% CI, 65%-96%), and 27% achieved a CR. Median PFS was 11.0 months (95% CI, 9.2-17.1), and median DOR was 9.4 months (95% CI, 7.4-15.3).

Regarding safety, the median time on treatment was 24.6 months. Hypertension (19.3%), aspartate aminotransferase elevation (10.2%), and alanine aminotransferase elevation (14.9%) were the most common treatment-emergent adverse events (TEAEs) of grade 3 or higher. Dose withholding, reduction, and discontinuation occurred in 70%, 49%, and 11%, respectively. TEAEs were fatal in 7% of patients, none of which were related to selpercatinib.

References

1. Gautschi O, Park K, Solomon BJ, et al. Selpercatinib in patients with RET fusion-positive non-small-cell lung cancer: updated safety and efficacy from the registrational LIBRETTO-001 phase I/II trial. Published online February 21, 2025. doi:10.1200/JCO-24-02076
2. A study of selpercatinib (LOXO-292) in participants with advanced solid tumors, RET fusion-positive solid tumors, and medullary thyroid cancer (LIBRETTO-001) (LIBRETTO-001). ClinicalTrials.gov. Updated February 28, 2025. Accessed March 14, 2025. https://tinyurl.com/ycxbrn8y