The central nervous system protective activity of selpercatinib from LIBRETTO-431

Fusions in the “rearranged during transfection” (RET) proto-oncogene are rare encompassing 1–2% of patients with non-small cell lung cancer (NSCLC) (1,2). RET fusions induce ligand-independent RET receptor tyrosine kinase activity and drives oncogenesis. Chemoimmunotherapy, in the form of platinum-doublet chemotherapy with anti-programmed death-1 (PD-1) monoclonal antibody (mAbs), improve outcomes of epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) wild-type NSCLC. However, NSCLC harbouring sensitising mutations in EGFR fail to benefit from the addition of anti-PD-1 mAbs (3,4), and targeted therapy is standard first-line therapy for EGFR mutated and ALK rearranged NSCLC. Selpercatinib, a tyrosine kinase inhibitor (TKI) targeting RET fusions, showed superior survival outcomes when compared to chemoimmunotherapy in the phase III LIBRETTO trial (5). Since NSCLC with sensitising driver alterations also have a tendency for brain metastases and cause significant quality of life issues for patients (6), protection from intracranial disease or events is of utmost importance. Selpercatinib already demonstrated brain penetrance in the single-arm LIBRETTO-001 trial, but there was no control arm to evaluate its intracranial efficacy (7). The initial LIBRETTO-431 trial publication reported on intracranial efficacy, however whether selpercatinib prevented new intracranial metastasis was not reported (7). With the demonstration of substantial central nervous system (CNS) protective effects for other TKIs, such as osimertinib and lorlatinib, this has contributed to these TKIs now being considered as potentially preferred first-line options for their respective driver sensitising NSCLCs (8,9). Therefore, it is imperative to demonstrate the CNS protective effect for selpercatinib as well. With a new update published in the Journal of Clinical Oncology in June 2024, Pérol et al. (10) aim to answer this important question.

The LIBRETTO-431 trial begun recruitment in March 2020 and ended in August 2022 (5). It was an open label, randomised, controlled phase III study that enrolled treatment naïve patients with advanced RET fusion NSCLC without other sensitising driver alterations. In the original publication, LIBRETTO-431 successfully met its primary outcome and demonstrated superiority of selpercatinib compared to platinum doublet chemotherapy ± pembrolizumab in the first-line treatment setting. Selpercatinib successfully doubled the median progression free survival [24.8 vs. 11.2 months; hazard ratio (HR): 0.46; 95% confidence interval (CI): 0.31–0.70; P<0.001] and demonstrated notable CNS activity. In the new update, Pérol et al. included and analysed 192 patients in the LIBRETTO-431 who had baseline brain imaging and treated with either selpercatinib or platinum doublet chemotherapy + pembrolizumab (chemoimmunotherapy). Of these patients, 150 did not have baseline CNS metastasis (99 received selpercatinib and 51 received chemoimmunotherapy) and 42 had baseline CNS metastasis (21 received selpercatinib and the other 21 received chemoimmunotherapy). In this post hoc analysis, Pérol et al. demonstrated the CNS protective effects of selpercatinib for patients without baseline CNS metastasis at 12 months, numerically (1.1% vs. 14.7%; HR, 0.17; 95% CI: 0.04–0.69), providing further evidence for selpercatinib as an appropriate first-line therapy. Moreover, with the favourable CNS outcomes, it will be interesting to evaluate the impact of selpercatinib as an adjuvant therapy (11) similar to osimertinib in the ADAURA study (12). Interestingly, out of the 19 participants with baseline CNS metastasis and received selpercatinib, the participants without prior CNS radiotherapy had higher objective response rates (ORR) compared to participants with prior CNS radiotherapy (93.3% vs. 50%). This suggests that radiotherapy may have changed the tumour microenvironment and made tumours less sensitive to TKIs and/or stabilised some CNS metastases since none of these patients had observed CNS disease progression. However, without translational data looking into the changes in the tumour microenvironment with tissue samples, it is difficult to determine the causality. Despite the small sample size, this observation is thought-provoking, and it is important to delineate the cause in the future as using combined modality treatments to enhance cancer therapy is on the rise.

The data from LIBRETTO-431 can also be contextualized with the reported outcomes for pralsetinib, another RET fusion targeting TKI that also demonstrated impressive CNS activity in the ARROW trial (13). Whilst direct comparisons cannot be performed, the ARROW trial demonstrated pralsetinib had an intracranial response rate of 70% (7/10 patients), with a median duration of intracranial response of 10.5 months. In this trial, among 223 patients without baseline CNS metastases, at the time of data cut-off only two patients had scan confirmed CNS progression. Currently, a phase 3 study in the first line setting for RET fusion advanced NSCLC is under way to confirm pralsetinib’s superiority towards chemoimmunotherapy (AcceleRET) (14). With a larger planned sample size of 471 (compared to LIBRETTO-431’s 261), 1:1 randomisation (instead of 2:1 in LIBRETTO-431), and a pre-planned intracranial response assessment, the AcceleRET trial may give clinicians more definitive answers regarding the CNS protective effect of pralsetinib. Given their contemporaneousness, a head-to-head trial between selpercatinib and pralsetinib is unlikely, and there may be future debates about which RET fusion targeting TKI has greater intracranial activity, like the multiple available ALK fusion targeting agents.

Limitations

In the study population without baseline CNS metastasis, the authors were unable to confirm if this translated into improved progression-free survival (PFS) or overall survival (OS), due to the limited sample size and immaturity of data. Moreover, the initial trial design only had patients with baseline CNS metastases undergo serial brain imaging upon follow up. Although amended later, this limited the sample size and thus power of the current study. In the study population with baseline CNS metastasis, despite numerical differences between the two groups in intracranial ORR and duration of response, the small sample size was too small to provide guidance in clinical practice. Study participants in this study also did not have strict and consistent brain imaging modality (a caveat with the post hoc analyses). The participants were either assessed using contrast computed tomography (CT) or magnetic resonance imaging (MRI) of the brain, which differ in the sensitivity of detecting CNS metastases. This further limits interpretation of the data.

Concluding remarks

Despite the limitations, this post hoc analysis looking at selpercatinib’s capability in CNS control adds value to our current knowledge. The intriguing observation that selpercatinib may have higher ORR without prior CNS radiotherapy needs further dissection. Furthermore, it is important to note that the chemoimmunotherapy arm had 3 complete responses out of 7 patients with RECIST measurable CNS disease. Therefore, this also raises the question whether selpercatinib given concurrently with chemotherapy may enhance intracranial ORR, similar to that demonstrated by the FLAURA2 trial for osimertinib ± chemotherapy (15). Ultimately however, the intracranial activity of selpercatinib with the prevention of CNS metastases to reduce morbidity and mortality for patients has substantial clinical significance.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, AME Clinical Trials Review. The article has undergone external peer review.

Peer Review File: Available at https://actr.amegroups.com/article/view/10.21037/actr-24-227/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-24-227/coif). A.C.T. reports consulting fees from Amgen, Bayer, Pfizer; research funding from AstraZeneca Takeda; and honoraria from Amgen, AstraZeneca, Daiichi Sankyo, Guardant, Janssen, Juniper Biologics, Pfizer, Roche, Takeda. The above are unrelated to the submitted work. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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