28MO - Predictive biomarkers of response to axitinib in patients with advanced EP-NETs enrolled in the AXINET trial (GETNE 1107): Underlying molecular mechanisms

Background

The AXINET trial demonstrated in 256 patients with extrapancreatic neuroendocrine tumors (EP-NETs) that axitinib + SSA (Somatostatin analogue) significantly improves ORR and PFS compared to placebo and SSA per central blinded assessment (Garcia-Carbonero et al, ESMO 2021). However, the benefit was limited and predictive biomarkers are necessary. Table: 28MO

The aim is to identify predictive signatures and underlying response mechanisms to axitinib in EP-NETs.

Methods

A predictive signature was developed using gene expression profiles of 126 FFPE tumours of 126 patients enrolled in the AXINET trial and the R package singscore. Genes most associated with clinical benefit in axitinib-treated patients based on PFS Cox regression and tumour shrinkage were selected. Gene set and cell type enrichment analysis was performed to unveil molecular mechanisms involved in axitinib response.

Results

A 9 gene transcriptomic signature (RPS10-NUDT3, MX2, C18orf25, SPP1, CLDN14, REXO1L2P, KLHDC3, ATXN7, CUBN) was developed based on their association with PFS (p <0.01) and its importance (VIP score) in tumour shrinkage. The signature score was significantly associated with tumour shrinkage (High vs Low, FC: 2.95; p< 0.0109) and PFS exclusively in axitinib-treated patients (H vs L, HR: 0.32, p< 0.001) but had no predictive value in the placebo arm (H vs L, HR: 0.84, ns). Pathways involved in the differential response to axitinib were EMT (H vs L, NES: -2.33; FDR =4.96∙10^-7) and Myc targets (H vs L, NES: -1.71; FDR =0.007). Finally, M1 macrophages were enriched in Low score patients (FDR =0.08) and neuron signature in High score patients (p =0.01).

Conclusions

We developed a 9-gene signature associated with axitinib benefit in EP-NETs which may be useful to select patients most likely to benefit from this therapy. Moreover, EMT, Myc targets and macrophages have been identified as potentially involved in the underlying mechanisms of response to this drug.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

Rocío García-Carbonero.

Funding

Pfizer.

Disclosure

B. Antón Pascual: Financial Interests, Personal, Advisory Role: AAA, Advanz, Merck, Servier, Novartis. J. Capdevila Castillon: Financial Interests, Personal, Invited Speaker: Novartis, Novartis, Pfizer, Ipsen, Exelixis, Bayer, Eisai, Advanced Accelerator Applications, Amgen, Sanofi, Lilly, Merck Serono; Financial Interests, Personal, Advisory Board: Pfizer, Ipsen, Exelixis, Bayer, Eisai, Advanced Accelerator Applications, Amgen, Sanofi, Lilly, Merck Serono; Financial Interests, Personal, Research Grant: Novartis, Pfizer, AstraZeneca, Advanced Accelerator Applications, Eisai, Bayer. E. Grande Pulido: Financial Interests, Personal, Invited Speaker: Adacap, AstraZeneca, Bristol Myers Squibb, Eisai, Eusa Pharma, Ipsen, Janssen, Lilly, Merck KGaA, Pfizer, Roche; Financial Interests, Personal, Advisory Board: Astellas, Bayer, MSD, Novartis, Sanofi Genzyme; Financial Interests, Institutional, Advisory Board: Caris Life Sciences, OncoDNA (Biosequence); Financial Interests, Institutional, Research Grant, Independent research grant: Astellas, AstraZeneca, Lexicon, MTEM/Threshold, NanoString Technologies, Pfizer, Roche, Merck; Financial Interests, Institutional, Invited Speaker, Independent research grant: Ipsen; Non-Financial Interests, Personal, Other, Ad Board Member: ENETS. R. Garcia-Carbonero: Financial Interests, Personal, Advisory Board: AAA, Advanz Pharma, Amgen, Bayer, BMS, HMP, Ipsen, Merck, Midatech, MSD, Novartis, PharmaMar, Pierre Fabre, Servier; Financial Interests, Institutional, Research Grant: BMS, MSD, Pfizer; Non-Financial Interests, Personal, Leadership Role, Global PI of investigator-initiated clinical trials (AXINET, NICENEC, PEMBROLA): BMS, MSD, Pfizer; Other, Personal, Other, Honoraria received by spouse for advisory board or invited speaker roles: Abbie, AstraZeneca, Bayer, Boehringer Ingelheim, BMS, Genomica, Lilly, MSD, Merck, Novartis, Pfizer, PharmaMar, Roche, Sanofi, Servier, Takeda. All other authors have declared no conflicts of interest.