In the phase 1/2 LIBRETTO-001 trial, selpercatinib demonstrated promising safety and efficacy in patients aged 18 years and older with RET-altered cancers.
Selpercatinib (LOXO-292) elicited clinically meaningful activity in patients with RET fusion-positive, tumor-agnostic cancer, according to updated findings of the phase 1/2 LIBRETTO-001 study (NCT03157128).1
Findings were published in the Lancet Oncology and showed that among the 41 evaluable patients included in the study, 18 had an objective response rate (ORR) as per the independent review committee of 43.9% (95% CI, 28.5-60.3). The agent also had a safety profile consistent with what was observed in previous indications.
Selpercatinib is a highly selective RET kinase inhibitor with CNS activity. The agent was developed to treat patients with RET-altered cancers and has previously shown preclinical activity in several RET fusion-positive models of lung, thyroid, and other cancers
“The efficacy of selpercatinib in this single-arm study was further supported by the intra-patient analyses comparing best response obtained on previous therapy to best response observed with selpercatinib, in which overall response and time on treatment were both shown to be improved with selpercatinib,” wrote the study authors led by Vivek Subbiah, MD, an associate professor in the Investigational Cancer Therapeutics department, and medical director of the Clinical Center for Targeted Therapy, Cancer Medicine division at The University of Texas MD Anderson Cancer Center.
The phase 1/2 LIBRETTO-001 is an ongoing, open-label, basket trial to evaluate selpercatinib in patients aged 18 years and older with RET-altered cancers.2
To be eligible for the trial, patients must have had disease progression on or post previous systemic therapies, no satisfactory therapeutic options, evaluable disease per RECIST version 1.1, a life expectancy of at least 3 months, and an ECOG performance status of 0-2.
Patients were administered oral selpercatinib in a continuous 28-day cycle. Those enrolled in phase 1, the dose-escalation portion of the trial, received between 20 mg once daily or 20-240 mg twice daily. In phase 2 of the trial, the recommended dose was determined to be 160 mg twice daily.
If a patient had a dose reduction due to an adverse event (AE), they were permitted to re-escalate upon resolution of that AE. Further, radiological tumor assessments were done at baseline, every 8 weeks for 1 year, and every 12 weeks thereafter, and response was determined according to RECIST 1.1 as assessed by the investigator and independent review committee.
Investigators evaluated objective response rate, determined by the independent review committee, as the primary end point of the trial. Secondary end points included clinical benefit rate, duration of response (DOR), time to response, time to best response, progression-free survival (PFS), overall survival (OS), and safety.
A total of 806 patients were enrolled in the LIBRETTO-001 trial between December 4, 2017, and August 4, 2021. Of these patients, 45 comprised the RET fusion-positive tumor-agnostic population. Twenty-six (58%) of the 45 patients enrolled had refractory gastrointestinal malignancies. Other histologies included in the trial were salivary, breast, sarcoma, xanthogranuloma, carcinoid, ovarian, pulmonary carcinosarcoma, and carcinoma of the skin.
The median number of previous systemic therapies was 2 (Interquartile range [IQR], 1.0-3.0), and 14 (31%) of the 45 patients received 3 or more prior systemic lines of therapy. A majority of the patients were female (n = 23; 51%), White (n = 31; 69%), and had an ECOG performance status of 1 (n = 27; 60%). A total of 37 (82%) patients had received prior chemotherapy, 5 patients (11%) had received prior multikinase inhibitors with some activity against RET kinase, and most RET fusions were identified using next-generation sequencing.
NCOA4 was the most common fusion partner as it was identified in 17 (38%) patients, and 1 patient with colorectal cancer had microsatellite instability-high (MSI-H) status prior to enrollment on the trial. Most patients (96%) were administered a starting dose of selpercatinib at the recommended dose of 160 mg twice daily. For the 2 patients who did not receive this dose, 1 was given a dose of 160 mg twice daily via intra-patient dose escalation and the other was given a starting dose of 120 mg twice daily which was never escalated.
Among the 45 patients enrolled, 41 (91%) were included in the efficacy analyses.Findings revealed the ORR was 43.9% (95% CI, 28.5-60.3) in 18 of 41 patients and a complete response was achieved in 2 (5%) of the 41 patients. The clinical benefit rate was 63.4% (95% CI, 46.9-77.9) in 26 of 41 patients, responses were observed in all histologies in which 2 or more patients were enrolled, and in 4 histologies where 1 patient was enrolled. The best response of stable disease was seen in the patient with colorectal cancer and MSI-H status
Median DOR was 24.5 months (95% CI, 9.2-not evaluable [NE]) as per the independent review committee and 18.4 months (9.2-NE) as per the investigator. Further, the median time to response was 1.9 months (IQR, 1.7-2.0), and the median time to best response was 1.9 months (IQR 1.8-2.0) as per the independent review committee and 1.9 months (1.8-3.5) as per the investigator.
The median PFS was 13.2 months (95% CI, 7.4-26.2) and 11.1 months (5.6-19.1) as per the independent review committee and investigator assessment. The median OS was 18.0 months (95% CI, 10.7-NE) and the estimated proportion of patients who were alive at 18 months was 51.7% (95% CI, 32.9-67.6).
At the time of data analysis, 18 (44%) patients continued receiving treatment with selpercatinib. The median duration of treatment was 11.0 months (95% CI, 3.7-NE). Among the 41 patients, 11 (27%) received selpercatinib treatment beyond progression on the basis of continued clinical benefit.
Regarding safety, findings showed that in the RET fusion-positive tumor-agnostic population (n = 45), the safety profile was consistent with what has been seen in previous reports and no new safety signals identified.
Treatment-related AEs led to permanent discontinuation of selpercatinib in 1(2%) patient, and treatment-emergent AEs (TEAEs) which occurred during study treatment were found to be related to selpercatinib.
The most common grade 3 or worse TEAEs consisted of hypertension (22%), increased alanine aminotransferase (16%), and increased aspartate aminotransferase (13%). Grade 5 treatment-emergent adverse events were observed in 3 (7%) patients with no grade 5 AS deemed to be related to treatment as per the investigator.
Treatment-emergent serious AEs were reported in 18 (40%) of 45 patients, including 3 (7%) which were related to selpercatinib. Further, the most common treatment-emergent serious AEs were abdominal pain, nausea, pyrexia, and vomiting, each of which occurred in 2 (4%) of 45 patients. The most common treatment-related serious AEs were drug-induced liver injury, fatigue, and hypersensitivity, each of which were observed in 1 (2%) of patients.