IFN-γ signature predicts response to immunotherapy

Preliminary results of the phase 1b DONIMI trial showed that the interferon (IFN)-γ signature is useful to discriminate between melanoma patients who will benefit from neoadjuvant therapy with nivolumab alone and patients who might need an escalated therapy.

Neoadjuvant immunotherapy with ipilimumab plus nivolumab induces high pathologic response rates (72–78%) in stage IIIB-D melanoma and is strongly associated with long-term relapse-free survival (RFS) [1]. Patients with a low baseline IFN-γ signature are known to be less likely to respond to immunotherapy [2]. The class I histone deacetylase inhibitor domatinostat has previously demonstrated to increase intertumoral T-cell infiltration and IFN-γ sign expression in melanoma. The DONIMI trial (NCT04133948) tests neoadjuvant combinations of nivolumab plus ipilimumab with domatinostat in melanoma patients stratified according to IFN-γ signature from tumour biopsies. Aim of the trial is to de-escalate neoadjuvant immunotherapy in patients with a high IFN-γ signature, whereas in patients with a low IFN-γ signature neoadjuvant immunotherapy will be escalated.

In the DONIMI study, stage III de novo or recurrent melanoma patients with a high IFN-γ signature (n=20) were randomised to arm A (2 cycles nivolumab 240 mg, every 3 weeks) or arm B (2 cycles nivolumab 240 mg plus domatinostat 200 mg twice daily, days 1–14, every 3 weeks), whereas patients with a low IFN-γ (n=20) were randomised to arm C (same treatment regimen as arm B) or arm D (2 cycles nivolumab 240 mg plus ipilimumab 80 mg plus domatinostat 200 mg once daily, days 1–14, every 3 weeks). Surgery and lymph node dissection was planned after 6 weeks. Adjuvant nivolumab 480 mg every 4 weeks or dabrafenib plus trametinib (in non-responding BRAF-mutated patients) started at week 12, for 52 weeks.

Prof. Christian Blank (Netherlands Cancer Institute, the Netherlands) presented the first results of the DONIMI trial [3]. All treatment regimens were feasible as surgery was performed on time in all patients (week 6 ± 1 week). Grade 3–4 systemic treatment-related adverse events during the first 12 weeks occurred in 0% in arm A, 20% in arm B, 40% in arm C, and 20% in arm D. Except for grade 2–3 domatinostat-related rash, no unexpected treatment-related adverse events were observed.

Pathologic response rate was 90% (70% pCR) in arm A and 80% (50% pCR) in arm B (high IFN-γ signature patients). This was 30% (10% pCR) in arm C, and 40% (30% pCR) in arm D (low IFN-γ signature patients). In arm D, 2 patients developed distant metastases before surgery. At data cut-off, estimated 6-month relapse-free survival rate was 100% in patients with high IFN-γ signature and 79.4% in patients with low IFN-γ signature.

Based on these preliminary results, Prof. Blank concluded that “neoadjuvant therapy with nivolumab plus domatinostat plus ipilimumab appears safe and feasible. Moreover, DONIMI shows prospectively the discriminative ability of the IFN-γ signature. It adequately identified patients who can benefit from nivolumab alone versus patients who might need an alternative scheme.”

1. Menzies AA, et al. Nat Med. 2021;27:301-309.
2. Karachaliou N, et al. Ther Adv Med Oncol. 2018;10:1758834017749748.
3. Blank CU, et al. Personalized combination of neoadjuvant domatinostat, nivolumab (NIVO) and ipilimumab (IPI) in stage IIIB-D melanoma patients (pts) stratified according to the interferon-gamma signature (IFN-γ sign): The DONIMI study. Abstract LBA39, ESMO Congress 2021, 16–21 September.

 

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Posted on 19 November, 202115 February, 2024