Pralsetinib: chemical and therapeutic development with FDA authorization for the management of RET fusion-positive non-small-cell lung cancers

Ali, Faraat; Neha, Kumari; Chauhan, Garima

doi:10.1007/s12272-022-01385-3

Cited by 8 publications

(16 citation statements)

References 98 publications

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“…Frequency of grade 3 or worse treatment-related AEs (42%) in our study cohort was comparable to that of the NSCLC population of the LIBRETTO-1 (28%; Drilon et al 2020) and ARROW (48%; Gainor et al 2021) study. Findings from the ARROW trial demonstrated that the most common grade 3 or worse treatment-related AEs in NSCLC patients were neutropenia (18%), hypertension (11%), and anaemia (10%) (Gainor et al 2021;Ali et al 2022); while in LIBRETTO-001 trial, the most common treatment-related AEs of grade 3 or 4 were hypertension (9%), increased ALT (9%), and increased AST level (6%) (Drilon et al 2020). In preclinical models, both selpercatinib and pralsetinib showed potent selective activity against RET with significantly diminished affinity for VEGFR2 (> 100-fold and 87-fold selectivity against VEGFR2, respectively), highlighting that off-target inhibition is minimized (Brandhuber et al 2016;Ali et al 2022).…”

Section: Discussionmentioning

confidence: 99%

“…Findings from the ARROW trial demonstrated that the most common grade 3 or worse treatment-related AEs in NSCLC patients were neutropenia (18%), hypertension (11%), and anaemia (10%) (Gainor et al 2021;Ali et al 2022); while in LIBRETTO-001 trial, the most common treatment-related AEs of grade 3 or 4 were hypertension (9%), increased ALT (9%), and increased AST level (6%) (Drilon et al 2020). In preclinical models, both selpercatinib and pralsetinib showed potent selective activity against RET with significantly diminished affinity for VEGFR2 (> 100-fold and 87-fold selectivity against VEGFR2, respectively), highlighting that off-target inhibition is minimized (Brandhuber et al 2016;Ali et al 2022). Although VEGFR2/KDR-related AEs ≥ grade 3 (skin toxicity and proteinuria) were not observed in treatment course of selective TKI due to their lower activity against VEGFR compared with MKIs (Subbiah et al 2020), ≥ grade 3 haematologic toxicity and hepatotoxicity were common.…”

Section: Discussionmentioning

confidence: 99%

“…There are two selective RET inhibitors currently being approved by FDA: pralsetinib and selperctatinib. The findings from the Phase I/II, global, multicenter, registrational ARROW trial (ClinicalTrials.gov Identifier: NCT03037385) revealed a high objective response rate (ORR) and a sustained median progression-free survival (mPFS) of pralsetinib in both previously treated (61%; 17.1 months) and untreated patients (70%; 9.1 months) (Gainor et al 2021;Ali et al 2022). Similarly, according to the registrational dataset analysis of a phase I/ II LIBRETTO-001 trial (ClincalTrials.gov identifier: NCT03157128), selpercatinib showed an ORR of 64% in pretreated RET fusion-positive NSCLC patients, and 85% in treatment-naïve patients (Drilon et al 2020).…”

Section: Introductionmentioning

confidence: 99%

“…Previous evidence has consistently shown that although both FDA Approved selective RET inhibitors are well tolerated, adverse events (AEs) are common in clinical trials. For pralsetinib, the most common any grade treatment-related AEs included elevated aspartate aminotransferase (AST) level (34%), anaemia (24%), elevated alanine aminotransferase (ALT) level (23%), and hypertension (22%); while for selpercatinib, the most observed the majority of treatment-related toxicities included diarrhoea (25%), increased AST (22%), increased ALT (20%), and hypertension (17%) (Drilon et al 2020;Gainor et al 2021;Ali et al 2022). These AEs can result in dose reduction, treatment discontinuation and, in some cases, these reactions can be lifethreatening.…”

Section: Introductionmentioning

confidence: 99%

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Selective RET inhibitors shift the treatment pattern of RET fusion-positive NSCLC and improve survival outcomes

Wei

Zhang

et al. 2022

J Cancer Res Clin Oncol

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Purpose Rearranged during transfection (RET) fusions are important genetic drivers in non-small cell lung cancer (NSCLC). Selective RET inhibitors are setting a new paradigm in RET-driven NSCLC. However, the real-world treatment patterns, outcomes and toxicity remain largely unknown. Methods Data from RET fusion-positive NSCLC patients treated in our centre were retrospectively analysed. Of them, patients diagnosed before and after August 2018 were included in analysis of treatment patterns; and patients received selective RET inhibitors were eligible for analysis of adverse events (AEs). Results Patients diagnosed before August 2018 (n = 30) predominantly received chemotherapy and immunotherapy (83%) as initial therapy, while patients diagnosed after August 2018 (n = 39) mainly received selective RET inhibitors (38.5% at first-line; 50.0% at second-line). In the total 69 patients, overall survival (OS) was prolonged in patients treated with selective RET inhibitors versus untreated patients (median 34.3 versus 17.5 months; p = 0.002) during a median follow-up of 28.7 months. But there was no difference between patients treated with immunotherapy versus untreated patients. In the 38 patients received selective RET inhibition, median progression-free survival (PFS) was 11.9 months. AEs ≥ grade 3 occurred in 42.1% patients and were not associated with PFS (p = 0.63) or OS (p = 0.60). Haematological toxicity ≥ grade 3 occurred in 31.6% patients and was the leading cause of drug discontinuation. Conclusion Selective RET inhibitors are increasingly being adopted into clinical practice and are associated with improved OS. However, treatment-related ≥ grade 3 AEs, especially haematologic AEs, occur frequently in real-world setting.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Selective RET inhibitors shift the treatment pattern of RET fusion-positive NSCLC and improve survival outcomes

Wei

Zhang

et al. 2022

J Cancer Res Clin Oncol

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“…Selpercatinib and pralsetinib effectively against RET alterations, including CCDC6-RET and KIF5B-RET fusions, RET activating mutations (C634W and M918T), and RET gatekeeper mutations V804L/M/E [ 18 , 19 ]. Remarkably, selpercatinib has > 100-times selectivity against VEGFR2, and pralsetinib has 87-times selectivity against VEGFR2 and 20-times selectivity against JAK1 [ 20 ]. Findings from the phase I/II LIBRETTO-001 trial (NCT03157128) demonstrated that selpercatinib has an overall response rate (ORR) of 64% in previously treated NSCLC patients and ORR of 85% in treatment-naïve RET -altered NSCLC patients [ 21 ].…”

Section: Introductionmentioning

confidence: 99%

RET fusions as primary oncogenic drivers and secondary acquired resistance to EGFR tyrosine kinase inhibitors in patients with non-small-cell lung cancer

et al. 2022

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Background RET fusions are rare oncogenic drivers in non-small cell lung cancer (NSCLC). While activating RET rearrangements are found in NSCLC patients harboring epidermal growth factor receptor (EGFR) genetic alterations at resistance to EGFR inhibitors, the extent to which co-occurring genomic alterations exist and how they might affect prognosis or therapy response is poorly understood. Methods Targeted next-generation sequencing (NGS) was used to assess 380 baseline patients with primary RET fusions and 71 EGFR-mutated NSCLC patients who acquired RET fusions after developing resistance to EGFR-tyrosine kinase inhibitors (EGFR-TKIs). Results Primary RET fusions were more likely associated with females and younger age, with KIF5B being the predominant fusion partner. In baseline patients, both SMAD4 (5.3% vs. 0.0%, P = 0.044) and MYC copy-number gain variants (6.9% vs. 0.0%, P = 0.009) were more frequently co-mutated with KIF5B-RET than CCDC6-RET. By contrast, CDKN2A (11.3% vs. 2.4%, P = 0.003) mutations were significantly enriched in CCDC6-RET-rearranged baseline patients. A significant increase in the proportion of CCDC6-RET was observed in acquired RET-rearranged patients (47.3% vs. 22.5%, P < 0.001). The median progression-free survival (PFS) of patients harboring RB1 and TP53 double-mutations (5.5 vs. 10.0 months, P = 0.020) or ERBB2 amplification (5.6 vs. 10.0 months, P = 0.041) was significantly shorter than the wild-type counterparts. Moreover, we identified that RET fusions were more likely associated with acquired resistance (AR) to third-generation EGFR-TKIs than previous generations of EGFR-TKIs. Conclusions In conclusion, we depicted the mutational profiles of NSCLC patients who harbor RET fusions at baseline or after resistance to EGFR-TKIs. Furthermore, our results suggest that RET fusions mediate secondary resistance to third-generation EGFR-TKIs and might be associated with poor prognosis in patients with NSCLC.

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Clinical evidence and adverse event management update of patients with RET- rearranged advanced non-small-cell lung cancer (NSCLC) treated with pralsetinib

Russo,

Bironzo,

Bennati

et al. 2024

Critical Reviews in Oncology/Hematology

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Pralsetinib: chemical and therapeutic development with FDA authorization for the management of RET fusion-positive non-small-cell lung cancers

Cited by 8 publications

References 98 publications

Selective RET inhibitors shift the treatment pattern of RET fusion-positive NSCLC and improve survival outcomes

Selective RET inhibitors shift the treatment pattern of RET fusion-positive NSCLC and improve survival outcomes

RET fusions as primary oncogenic drivers and secondary acquired resistance to EGFR tyrosine kinase inhibitors in patients with non-small-cell lung cancer

Clinical evidence and adverse event management update of patients with RET- rearranged advanced non-small-cell lung cancer (NSCLC) treated with pralsetinib

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