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

Abstract

Background: Selpercatinib is a first-in-class, highly selective RET kinase inhibitor with CNS activity that has shown efficacy in RET fusion-positive lung and thyroid cancers. RET fusions occur rarely in other tumour types. We aimed to investigate the efficacy and safety of selpercatinib in a diverse group of patients with RET fusion-positive non-lung or thyroid advanced solid tumours (ie, a tumour-agnostic population).

Methods: LIBRETTO-001 is an ongoing phase 1/2, single-group, open-label, basket trial of selpercatinib in patients aged 18 years and older (or ≥12 years, where permitted by regulatory authorities) with RET-altered cancers. The trial is being conducted at 89 sites in 16 countries; the tumour-agnostic population was enrolled at 30 sites (outpatient and inpatient medical facilities) across eight countries. A prespecified interim analysis of LIBRETTO-001 was planned to investigate the efficacy and safety of selpercatinib in a tumour-agnostic population of patients with RET fusion-positive advanced solid tumours; the data cutoff date was Sept 24, 2021. Eligible patients had disease progression on or after previous systemic therapies or no satisfactory therapeutic options and an Eastern Cooperative Oncology Group performance status of 0-2. Selpercatinib was orally administered in a continuous 28-day cycle. Patients enrolled in the phase 1 dose-escalation portion received between 20 mg once daily or 20-240 mg twice daily; the phase 2 recommended dose was 160 mg twice daily. The primary endpoint was the objective response rate as determined by the independent review committee. The efficacy-evaluable tumour-agnostic population was defined as patients with RET fusion-positive cancer, other than non-small-cell lung cancer and thyroid cancer, who had at least 6 months of follow-up from the first study dose at the time of data cutoff (all responders at the time of data cutoff were followed up for at least 6 months from the onset of response unless they progressed or died earlier). Safety was analysed in the tumour-agnostic population of patients who had been enrolled and received selpercatinib on or before the data cutoff date. This study is registered with ClinicalTrials.gov (NCT03157128) and is still recruiting participants.

Findings: Between Dec 4, 2017, and Aug 4, 2021, 45 patients with RET fusion-positive tumour-agnostic cancers were enrolled from the phase 1 dose-escalation and phase 2 dose-expansion cohorts of the trial. 43 (96%) of 45 patients received a starting dose of selpercatinib at the recommended dose of 160 mg twice daily. Of the two patients who did not, one received a dose of 160 mg twice daily via intra-patient dose escalation (as allowed per protocol for patients enrolled in the phase 1 portion of the study at lower doses) and the other patient's starting dose of 120 mg twice daily was never escalated. Of the 41 efficacy-evaluable patients, the objective response rate as per the independent review committee was 43·9% (95% CI 28·5-60·3; 18 of 41 patients). The most common grade 3 or worse treatment-emergent adverse events were hypertension (ten [22%] of 45 patients), increased alanine aminotransferase (seven [16%]), and increased aspartate aminotransferase (six [13%]). Treatment-emergent serious adverse events occurred in 18 (40%) of 45 patients. No treatment-related deaths occurred.

Interpretation: Selpercatinib showed clinically meaningful activity in the RET fusion-positive tumour-agnostic population, with a safety profile consistent with that observed in other indications. Comprehensive genomic testing that includes RET fusions will be crucial for identifying patients who might benefit from selpercatinib.

Funding: Loxo Oncology.

Figure 1.. Trial Profile

Four patients were excluded from the efficacy-evaluable population because they did not meet the criteria for follow-up time (received the first dose after March 24, 2021). NSCLC=non-small-cell lung cancer.

Figure 2.. Response to selpercatinib

(A) Waterfall plot of maximum change in tumour size for the 35 evaluable patients with RET fusion-positive solid tumours as per the independent review committee. (B) Waterfall plot of maximum change in tumour size for the 35 evaluable patients with RET fusion-positive solid tumours as per investigator assessment. Vertical bars represent the best percentage change from baseline in the sum of diameters for all target lesions. Progressive disease (+20%) and partial response (–30%) are indicated with dashed lines. The waterfall plot excludes patients with no measurable disease (n=5) or no post-baseline lesion measurements (n=1). Two patients (one with pancreatic and one with salivary cancer) who had a 100% reduction in measurable target lesions were determined to have an overall partial response. One additional patient with breast cancer had no measurable disease (not shown on the plot) and was determined to have a complete response. (C) Time on treatment. The swimmer plot depicts duration of treatment and time to response in patients as per the independent review committee. The time at which the first response was observed is indicated with circles. *Starting dose: 80 mg twice daily. †Starting dose: 120 mg twice daily.

Figure 2.. Response to selpercatinib

(A) Waterfall plot of maximum change in tumour size for the 35 evaluable patients with RET fusion-positive solid tumours as per the independent review committee. (B) Waterfall plot of maximum change in tumour size for the 35 evaluable patients with RET fusion-positive solid tumours as per investigator assessment. Vertical bars represent the best percentage change from baseline in the sum of diameters for all target lesions. Progressive disease (+20%) and partial response (–30%) are indicated with dashed lines. The waterfall plot excludes patients with no measurable disease (n=5) or no post-baseline lesion measurements (n=1). Two patients (one with pancreatic and one with salivary cancer) who had a 100% reduction in measurable target lesions were determined to have an overall partial response. One additional patient with breast cancer had no measurable disease (not shown on the plot) and was determined to have a complete response. (C) Time on treatment. The swimmer plot depicts duration of treatment and time to response in patients as per the independent review committee. The time at which the first response was observed is indicated with circles. *Starting dose: 80 mg twice daily. †Starting dose: 120 mg twice daily.

Figure 3.. Kaplan-Meier plots

(A) Duration of response per independent review committee. (B) Duration of response per investigator. (C) Progression-free survival per independent review committee. (D) Progression-free survival per investigator. (E) Overall survival per investigator. Tick marks indicate censored data. NE=not evaluable.

Figure 3.. Kaplan-Meier plots

(A) Duration of response per independent review committee. (B) Duration of response per investigator. (C) Progression-free survival per independent review committee. (D) Progression-free survival per investigator. (E) Overall survival per investigator. Tick marks indicate censored data. NE=not evaluable.