Reported by Dr Willem Lybaert, VITAZ Sint-Niklaas and University Hospital Antwerp
The LIBRETTO-531 study was specifically structured to explore the optimal primary treatment approach for individuals diagnosed with advanced medullary thyroid carcinoma (MTC). The study involved a meticulous comparison between selpercatinib and the prevailing standard treatments employing cabozantinib or vandetanib. Remarkably, the administration of selpercatinib led to a significant surge in PFS, TFFS and ORR. Notably, the side effect profile of selpercatinib indicated enhanced tolerability. These compelling findings were promptly disseminated through publication in the New England Journal of Medicine, underscoring the viability of selpercatinib as a primary treatment for advanced RET-mutant MTC. The study underscored the crucial importance of swift and accurate RET testing protocols to adeptly identify suitable candidates for this treatment regimen.
Conversely, the CABATEN study encompassed multiple cohorts of diverse NETs to assess the efficacy and safety of combining cabozantinib with atezolizumab post-standard treatment within each cohort. While the overall results did not exhibit exceptional outcomes, discernible activity was observed in adrenocortical and anaplastic thyroid carcinoma. Notably, the study lacked pertinent immunotherapy markers critical for identifying NETs patients who might derive substantial benefits from these treatments. Despite these limitations, the study remains important, offering crucial signals that necessitate further investigation and in-depth analysis.
In the CABINET study, patients afflicted with well-differentiated NETs (grades 1-2-3) post-standard treatment were subjected to a comparative analysis involving cabozantinib versus a placebo. Encouragingly, the outcomes provided reassurance, revealing a notable increase in PFS among heavily pretreated pNET and epNET patients. However, it is imperative to note that grade 3-4 toxicities manifested in 60% of patients, highlighting the imperative need for assessing the QoL in this patient population. Therefore, we hope for the incorporation of cabozantinib into treatment protocols for these patients in Europe.
Additionally, studies with limited impact were presented. The MGMT-NET study explored the role of MGMT status in predicting the outcomes of alkylating agent-based versus oxaliplatin-based chemotherapy in advanced NETs. Regrettably, the study did not yield significant benefits in terms of ORS, PFS and OS. This necessitates further investigation, as the detection of MGMT expression in NETs might yet prove pivotal in determining the most efficacious treatment regimens for this patient population.
In the EOADR1-19/SPENCER study focused on MPP in which a combination of immunotherapy with a vaccine was administered. While the response rate was not striking, the combination did exhibit prolonged stabilisation of cold tumours. Consequently, the underlying concept of this treatment modality remains under investigation.
Within the EVINEC study, patients afflicted with high-grade tumours were treated with everolimus following platinum-based chemotherapy. Encouragingly, everolimus demonstrated efficacy in NET G3, although similar benefits were not observed in neuroendocrine carcinoma. While no new safety concerns were reported, further research is imperative to comprehensively compare its efficacy with alternative treatments.
The AVENEC and CABOAVENEC trials involved the administration of avelumab alone or in combination with cabozantinib in NEN G3 patients. While some positive signals were discerned, additional investigation is warranted, alongside the identification of biomarkers crucial for delineating patients who could substantially benefit from immunotherapy after aggressive chemotherapy. Presently, the specific patient demographic that stands to gain the most from these interventions remains indeterminate.
Moreover, a noteworthy concept under exploration pertains to Delta-Like Ligand 3 (DLL3), a protein extensively expressed in small lung cancers and various neuroendocrine tumours. This study, conducted in the phase 1 setting, demonstrated the efficacy of blocking DLL3, presenting a promising avenue for further investigation and potential therapeutic development.
In the context of locally advanced pancreatic NETs where resection remains on the cusp of feasibility, the NeoLuPaNET study probed the impact of neoadjuvant PRRT on tumour size. The study revealed that PRRT is safe, enabling the feasibility of subsequent surgical intervention. Nevertheless, the comparative efficacy of PRRT versus chemotherapy as the most efficacious neoadjuvant necessitates further exploration. This approach represents a compelling concept for future studies, signalling a paradigm shift towards earlier lines of intervention in the treatment continuum.
References:
Hadoux J. – Randomized phase III study of selpercatinib versus cabozantinib or vandetanib in advanced, kinase inhibitor-naïve, RET-mutant medullary thyroid cancer. ESMO2023 – LBA3
Capdevila Castillon J. – Cabozantinib plus Atezolizumab in Advanced and Progressive Neoplasms of the Endocrine System: A multi-cohort Basket Phase II Trial (CABATEN / GETNE-T1914). ESMO2023 – 723O
Chan J. – Alliance A021602: Phase III, double-blinded study of cabozantinib versus placebo for advanced neuroendocrine tumors (NET) after progression on prior therapy (CABINET). ESMO2023 – LBA53
Walter T. – Alkylating agent-based vs oxaliplatin-based chemotherapy in neuroendocrine tumours according to the O6-methylguanine-DNA methyltransferase (MGMT) status: A randomized phase II study (MGMT-NET) on behalf of the French Group of Endocrine Tumors (GTE) and ENDOCAN-RENATEN network. ESMO2023 – LBA54
Baudin E. – EO2401 (E) peptide immunotherapy + nivolumab (N) in adrenocortical carcinoma (ACC) and metastatic pheochromocytoma/paraganglioma (MPP): EOADR1-19/SPENCER. ESMO2023 – 724O
Pavel M. – Safety and efficacy of everolimus (EVE) as second-line treatment in neuroendocrine neoplasms G3 (NEN G3): An AIO phase II study (EVINEC). ESMO2023 – 1184MO
Weber M. – Activity and safety of avelumab alone or in combination with cabozantinib in patients with advanced high grade neuroendocrine neoplasias (NEN G3) progressing after chemotherapy. The phase II, open-label, multicenter AVENEC and CABOAVENEC trials. ESMO2023 – 1185MO
Gambardella V. – Phase I trial of the DLL3/CD3 IgG-like T cell engager BI 764532 in patients (pts) with DLL3-positive (+) tumours: Focus on neuroendocrine carcinomas. ESMO2023 – 725MO
Partelli S. – A prospective phase II single-arm trial on neoadjuvant peptide receptor radionuclide therapy (PRRT) with 177Lu-DOTATATE followed by surgery for pancreatic neuroendocrine tumors (NeoLuPaNET). ESMO2023 – 1186MO
With the educational support of:
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