Prof Herbert Loong: LIBRETTO 431

Background:

Prof Herbert Loong, representing the Chinese University of Hong Kong, presented a late-breaking abstract at ESMO 2023, the LIBRETTO 431 trial. This trial investigates the use of selpercatinib, a selective RET kinase inhibitor, in the first-line treatment of RET fusion-positive NSCLC. RET fusion is a rare alteration found in only 2% of NSCLC patients. Previous studies, such as the Liberator 001 trial, showed promising responses to selpercatinib in treatment-naive patients, with response rates exceeding 80%. However, the current standard of care remains pembrolizumab plus pemetrexed plus carboplatin.

Study Design:

The LIBRETTO 431 trial is a head-to-head, open-label, randomised Phase 3 trial comparing selpercatinib with the standard of care. Patients with Stage IIIB, IIIC, and Stage 4 non-squamous non-small cell lung cancer were included, provided they had an ECOG performance status of 0-2 and were treatment-naive. The trial allowed patients with brain metastasis but excluded those with symptomatic brain metastasis. Randomisation was stratified based on the presence of brain metastasis and geographical location. Investigators were given the discretion to choose pembrolizumab for patients in the control arm. At least 80% of patients in the control arm were planned to receive pembrolizumab, known as the intention-to-treat pembrolizumab population. Initially, a one-to-one randomisation was planned, but it was later amended to a two-to-one randomisation, with patients receiving selpercatinib or the chemotherapy control, with or without pembrolizumab.

Primary Endpoints:

The primary endpoint of the trial was a dual-gated assessment of PFS by Blind Independent Central Review for both the intention-to-treat pembrolizumab group and the overall population. Secondary endpoints included survival, intracranial survival, safety, and patient-reported outcomes.

Results:

The trial demonstrated that selpercatinib was effective, with PFS favouring selpercatinib. The median PFS in the selpercatinib arm was 24.8 months compared to 11.2 months in the control arm, representing a significant improvement (hazard ratio 0.46). Similar results were observed in the overall population. Selpercatinib effectively controlled brain metastasis, with lower rates of brain metastasis development in patients initially without such metastasis.

Safety Profile:

As expected, common toxicities included AST-ALT changes, peripheral oedema, and hypertension. These toxicities were manageable with dose interruptions and adjustments to the dosing schedule. The control arm exhibited myelosuppression.

Patient-Reported Outcomes:

Selpercatinib showed favourable outcomes in terms of delayed symptom onset and improved overall function for patients.

Conclusion:

In conclusion, the LIBRETTO 431 trial confirmed the efficacy of selpercatinib in the first-line treatment of RET fusion-positive NSCLC. It demonstrated superior activity compared to the standard of care, effectively prevented brain metastasis, and was well-tolerated. The results underscore the importance of early identification of suitable patients through next-generation sequencing testing, given that RET fusion is a rare alteration, affecting only 2% of the population. Next-generation sequencing testing is crucial to ensure that the survival benefits of selpercatinib are extended to this small population of RET fusion non-small cell lung cancer patients.