Case Report: Complete pathologic response to neoadjuvant selpercatinib in a patient with resectable early-stage RET fusion-positive non-small cell lung cancer.

The LIBRETTO-001 trial demonstrated the activity of the selective rearrangement during transfection (RET) inhibitor selpercatinib in advanced RET fusion-positive non-small cell lung cancer (NSCLC) and resulted in the drug's approval for this indication. A cohort that included neoadjuvant and adjuvant selpercatinib was opened on LIBRETTO-001 for early-stage RET fusion-positive NSCLC with the primary endpoint of major pathologic response. A patient with a stage IB (cT2aN0M0) KIF5B-RET fusion-positive NSCLC received 8 weeks of neoadjuvant selpercatinib at 160 mg twice daily followed by surgery. While moderate regression in the primary tumor (stable disease, Response Evaluation Criteria in Solid Tumors (RECIST) guidelines version 1.1) was observed radiologically, assessment via an Independent Pathologic Review Committee revealed a pathologic complete response (0% viable tumor). This consensus assessment by three independent pathologists was aided by RET fluorescence in situ hybridization testing of a reactive pneumocyte proliferation showing no rearrangement. Neoadjuvant selpercatinib was well-tolerated with only low-grade treatment-emergent adverse events. The activity of prospective preoperative selpercatinib in this case establishes proof of concept of the potential utility of RET inhibitor therapy in early-stage RET fusion-positive NSCLC.

Selpercatinib in Patients With RET Fusion-Positive Non-Small-Cell Lung Cancer: Updated Safety and Efficacy From the Registrational LIBRETTO-001 Phase I/II Trial.

PURPOSE: Selpercatinib, a first-in-class, highly selective, and potent CNS-active RET kinase inhibitor, is currently approved for the treatment of patients with RET fusion-positive non-small-cell lung cancer (NSCLC). We provide a registrational data set update in more than double (n = 316) of the original reported population (n = 144) and better characterization of long-term efficacy and safety. METHODS: Patients were enrolled to LIBRETTO-001, a phase I/II, single-arm, open-label study of selpercatinib in patients with RET-altered cancers. An analysis of patients with RET fusion-positive NSCLC, including 69 treatment-naive and 247 with prior platinum-based chemotherapy, was performed. The primary end point was objective response rate (ORR; RECIST v1.1, independent review committee). Secondary end points included duration of response (DoR), progression-free survival (PFS), overall survival, and safety. RESULTS: In treatment-naive patients, the ORR was 84% (95% CI, 73 to 92); 6% achieved complete responses (CRs). The median DoR was 20.2 months (95% CI, 13.0 to could not be evaluated); 40% of responses were ongoing at the data cutoff (median follow-up of 20.3 months). The median PFS was 22.0 months; 35% of patients were alive and progression-free at the data cutoff (median follow-up of 21.9 months). In platinum-based chemotherapy pretreated patients, the ORR was 61% (95% CI, 55 to 67); 7% achieved CRs. The median DoR was 28.6 months (95% CI, 20.4 to could not be evaluated); 49% of responses were ongoing (median follow-up of 21.2 months). The median PFS was 24.9 months; 38% of patients were alive and progression-free (median follow-up of 24.7 months). Of 26 patients with measurable baseline CNS metastasis by the independent review committee, the intracranial ORR was 85% (95% CI, 65 to 96); 27% were CRs. In the full safety population (n = 796), the median treatment duration was 36.1 months. The safety profile of selpercatinib was consistent with previous reports. CONCLUSION: In a large cohort with extended follow-up, selpercatinib continued to demonstrate durable and robust responses, including intracranial activity, in previously treated and treatment-naive patients with RET fusion-positive NSCLC.

Comparative Effectiveness of First-Line Selpercatinib versus Standard Therapies in Patients with RET-Activated Cancers: An Exploratory Interpatient Analysis of LIBRETTO-001.

Selpercatinib is indicated for locally advanced/metastatic RET-activated solid tumors after progression or following prior systemic therapies. Until the recently published data from LIBRETTO-431 and LIBRETTO-531, there were limited effectiveness data comparing selpercatinib with other first-line treatments in RET-activated non-small cell lung cancer (NSCLC), medullary thyroid cancer (MTC), and thyroid cancer (TC). This study analyzed patient data from LIBRETTO-001 and compared the outcomes (time to treatment discontinuation {TTD}, time to next treatment or death {TTNT-D}, time to progression {TTP}, and the objective response rate {ORR}) of first-line selpercatinib (selpercatinib arm) use with the outcomes of first-line standard therapies in patients who then received selpercatinib in later lines of treatment (comparator arm). Overall, the first-line selpercatinib arm had a longer TTD, TTNT-D, and TTP versus the first-line comparator arm. The hazard ratios (HRs) for TTD were 0.29 (NSCLC), 0.15 (MTC), 0.08 (TC); for TTNT-D, the HRs were 0.48 (NSCLC), 0.11 (MTC), 0.09 (TC); and for TTP, the HRs were 0.54 (NSCLC), 0.15 (MTC), and 0.12 (TC). The ORR was higher for first-line selpercatinib versus the first-line comparator (NSCLC: 85.3% vs. 39.7%; MTC: 82.6% vs. 15.2%; and TC: 81.8% vs. 31.8%). First-line selpercatinib use is associated with improved outcomes compared to first-line comparator therapies for patients with advanced/metastatic RET-activated cancers.

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.

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.

Increased estrogen receptor beta expression correlates with decreased spine formation in the rat hippocampus.

Estrogens play an important role in the brain function acting through two receptor types, ERalpha and ERbeta, both well-recognized as transcription factors. In this study, we investigated the ERbeta mRNA and protein levels in the rat hippocampus by using two in vivo models that are known to affect synapse formation. Natural estrous-proestrous cycle was used as a model in which a marked decrease in the density of hippocampal synapses was previously observed between proestrus and estrus. We have found that ERbeta mRNA and protein were displayed in high levels in the estrus and in low levels in the proestrous phase. By applying kainic acid (KA) to adult rats, we demonstrated that up-regulation of ERbeta mRNA and protein in hippocampal CA regions was vulnerable to KA-induced excitotoxicity. Furthermore, we note a concomitant decrease of ERbeta in the excitotoxicity-resistant denate gyrus that undergoes intense plastic changes, including synaptogenesis. These data suggested that decreases in ERbeta expression correlated with increase in synapse formation. This notion has been tested in vitro in hippocampal cultures, in which overexpression of ERbeta by means of gene transfection resulted in the lowering of the dendritic spine density that was elevated by estrogen. In summary, our results suggest that ERbeta inhibits synapse formation in hippocampal neurons.

Non-nuclear estrogen receptor beta and alpha in the hippocampus of male and female rats.

Estrogens play important roles in the brain, acting through two receptor types, ERalpha and ERbeta, both recognized as transcription factors. In this study, we investigated the ERbeta mRNA and protein expression in the male and female rat brain, focusing on the hippocampus, and comparing with well-known ERalpha expression patterns. Extranuclear ERbeta localization, as shown by light microscopic immunocytochemistry and tissue fractionation experiments, was noted in the hippocampus, whereas nuclear ERbeta was present in the amygdala. Despite these marked differences in subcellular localizations, similar expression levels of ERbeta proteins as well as the profile of ERbeta mRNA isoforms were observed in the two brain structures. ERalpha was localized to the nucleus more so than ERbeta, yet not without an extranuclear component. Our results suggest that cytoplasmic estrogen receptors may play an important role in hippocampal physiology.

Evaluation of mRNA expression of estrogen receptor beta and its isoforms in human normal and neoplastic endometrium.

Endometrial cancer is well known to be estrogen-dependent. Two estrogen receptor types, ERalpha and ERbeta, are major mediators of a diversity of biologic functions of estrogen and play an important role in estrogen-dependent tissues and cancers. Cloning of ERbeta was followed by the discovery of a variety of its isoforms. Using real-time RT-PCR, the relative expression levels of ERbeta1, ERbeta2 (ERbetacx), ERbeta3, ERbeta4 and ERbeta5 were studied. We observed coexpression of ERbeta isoforms in the endometrium and upregulation of the ERbeta5 transcript in malignant endometrium. We also observed downregulation of ERbeta2Delta5 transcript in neoplastic endometrium, using a semiquantitative method. Our results suggest that analyzing the changes in ERbeta and its isoforms may be important in the diagnosis, prognosis and treatment of endometrial cancer.

[Estrogen receptors in the brain]. / Receptory estrogenowe w mózgu.

Estrogen plays an important role in changes taking place in the brain through the regulation of growth and differentiation of axons and dendrites, influence on plasticity, support of survival as well cognitive and behavioral functions. The classical mode of estrogen action is through the activation of its receptors, transcription factors. Two such estrogen receptors have been cloned, ER alpha i ER beta. Several isoforms of ER beta have also been characterized, which may be a significant factor in the regulation of estrogen response in the brain. Additionally, actions of estrogens through membrane or intra-cellular receptors, are suggested. The functions played by ER alpha i ER beta in the brain may be explored by studies on ER alpha or ER beta knockout mice. The results of these studies point to the role of ER alpha in reproductive functions, while ER beta seems to be important in cognitive processes. Autoradiography, immunohistochemistry, and in situ hybridization have been employed in the localization of estrogen receptors in the brain. Aside from demonstrating differences in the localization and expression levels of both receptors, these studies have proven, that both ER alpha i ER beta are able to bind estrogen. However, the pattern of expression of estrogen receptors in the brain is not static, but undergoes rapid changes in response to injury. Many studies point to a wide range of estrogen actions in the brain. For that reason, a complementary mechanism of action of estrogen is proposed, based on their interaction with various growth factors, as well as on the synergistic action of this hormone through, both, the estrogen receptors and estrogen-independent pathways.

Matrix metalloproteinases in the adult brain physiology: a link between c-Fos, AP-1 and remodeling of neuronal connections?

Matrix metalloproteinases (MMPs), together with their endogenous inhibitors (TIMPs) form an enzymatic system that plays an important role in a variety of physiological and pathological conditions. These proteins are also expressed in the brain, especially under pathological conditions, in which glia as well as invading inflammatory cells provide the major source of the MMP activity. Surprisingly little is known about the MMP function(s) in adult neuronal physiology. This review describes available data on this topic, which is presented in a context of knowledge about the MMP/TIMP system in other organs as well as in brain disorders. An analysis of the MMP and TIMP expression patterns in the brain, along with a consideration of their regulatory mechanisms and substrates, leads to the proposal of possible roles of the MMP system in the brain. This analysis suggests that MMPs may play an important role in the neuronal physiology, especially in neuronal plasticity, including their direct participation in the remodeling of synaptic connections-a mechanism pivotal for learning and memory.