Promising Selpercatinib Data Highlight Value of RET Fusion Testing for Patients With Solid Tumors


Selpercatinib demonstrated a promising efficacy profile in patients with RET-fusion positive solid tumors.

Vivek Subbiah, MD

Vivek Subbiah, MD

Favorable objective responses were observed among patients with RET fusion–positive solid tumors who received selpercatinib (Retevmo), according to an interim analysis of the ongoing phase 1/2 LIBRETTO-001 trial (NCT03157128). The positive clinical responses observed in these patients underscores the importance of comprehensive genomic testing in this setting, the study authors noted.

At a prespecified interim analysis, the objective response rate (ORR) associated with selpercatinib was 43.9% (95% CI, 28.5%-60.3%; n = 18/41). The most frequently reported treatment-emergent adverse events (TRAEs) included hypertension (22%), increased alanine aminotransferase (16%), and increased aspartate aminotransferase (13%). Serious TRAEs were reported in 40% of patients, but no treatment-related deaths occurred.

“The activity of selpercatinib in a broad variety of RET fusion–positive solid tumors is clinically meaningful, providing durable responses in patients previously treated with standard-of-care therapies, or for whom no standard of care exists,” wrote Vivek Subbiah, MD, associate professor in the Department of Investigational Cancer Therapeutics and Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center, and coinvestigators in a recent paper published in Lancet Oncology. “These findings emphasize the importance of broad-based genomic profiling to identify patients with RET fusions who might benefit from selpercatinib treatment.”

Selpercatinib is a RET kinase inhibitor which has demonstrated intracranial nervous system activity. It has also demonstrated preclinical activity in RET fusion–positive lung and thyroid cancers.

Based on initial findings from the LIBRETTO-001 trial, the FDA granted selpercatinib accelerated approval to treat patients with solid tumor harboring a RET gene fusion mutation. This open-label, basket trial of selpercatinib enrolled patients aged 18 years or older who had an ECOG performance status of 0 to 2. Patients received oral selpercatinib in a continuous 28-day cycle. In the phase 1 dose-escalation study, patients received 20 mg once daily or 20-240 mg twice daily. In the phase 2 setting, patients received 160 mg twice daily.

A total of 806 patients were enrolled into LIBRETTO-001, of whom 45 tested positive for a RET fusion. In this specific cohort, 58% (n = 26) had refractory gastrointestinal malignancies, other diagnoses in this cohort included salivary, breast, sarcoma, xanthogranuloma, carcinoid, ovarian, pulmonary carcinosarcoma, and carcinoma of the skin. All patients with RET fusion–positive disease had received a median of 2 prior systemic therapies. Fourteen of these patients had been pretreated with at least 3 prior therapies.

Almost all patients (96%) initiated treatment at the recommended selpercatinib dose of 160 mg twice daily. One of the 2 patients who started on a reduced dose successfully escalated their treatment up to a 160 mg twice daily dose. The other patient continued with their reduced dose of 120 mg twice daily throughout treatment.

In addition to favorable ORR and safety data, this analysis provided updates on clinical benefit outcomes, duration of response, time to response, progression-free survival (PFS), and overall survival (OS).

A complete response was reached in 2 patients (5%) and the clinical benefit (defined as the proportion of patients with a best overall response of complete response, partial response, or stable disease lasting ≥ 16 weeks) was 63.4% (95% CI, 46.9%-77.9%; n = 26/41).

The median duration of response was 24.5 months (95% CI, 9.2-not evaluable [NE]) according to independent review committee and 18.4 months (9.2-NE) according to investigators. Moreover, the median time to best response was 1.9 months, according to both the independent review committee and the investigators.

According to the independent review committee, the median PFS with selpercatinib was 13.2 months (95% CI, 7.4-26.2), with a 1-year PFS rate of 53.1% (95% CI, 34.1%-68.8%), and a 2-year PFS rate of 32.1% (95% CI, 14.0%-51.7%). Median OS was 18.0 months (95% CI, 10.7-NE) and at 18 months the estimated OS rate was 51.7% (95% CI, 32.9%-67.6%).

The safety profile was reported to be consistent with previous findings; a total of 3 patient developed grade 5 TEAEs (7%). The most common serious TREAEs included abdominal pain, nausea, pyrexia, and vomiting.Patients also experienced drug-induced liver injury, fatigue, and hypersensitivity because of treatment.

“RET alterations are clinically validated actionable oncogenic drivers in lung and thyroid cancers, and selpercatinib has been shown to be beneficial for patients with these diseases,” study authors concluded. “This study shows that RET fusions are oncogenic drivers in other cancers and that selpercatinib is a potentially effective treatment for RET fusion–positive cancers regardless of tumor type.”


Subbiah V, Wolf J, Konda B, et al. Tumour-agnostic efficacy and safety of selpercatinib in patients with RET fusion-positive solid tumours other than lung or thyroid tumours (LIBRETTO-001): a phase 1/2, open-label, basket trial. Lancet Oncol. 2022;23(10):1261-1273. doi:10.1016/S1470-2045(22)00541-1

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