Oncology Xagena

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Ibrutinib, a Bruton’s tyrosine kinase inhibitor, in combination with PD-1 inhibitor Nivolumab in patients with metastatic solid tumors

Myeloid-derived suppressor cells ( MDSC ) are expanded in cancer and promote immune suppression.
A research has shown that Ibrutinib ( Imbruvica ) inhibits migration and immunosuppressive function of MDSC.

Moreover, the combination of Ibrutinib and a PD-L1 inhibitor has been found to have synergistic anti-tumor effects in a multiple solid tumor mouse models.
Therefore, researchers have conducted a pilot study testing the combination of Ibrutinib and Nivolumab ( Opdivo ) in patients with metastatic solid tumors.

Sixteen patients with advanced solid tumors were recruited to this trial.
Ibrutinib was dosed as an oral single agent, starting 7 days prior to cycle 1 of Nivolumab and given until cycle 1, day 8 of Nivolumab.
Nivolumab was administered intravenously on days 1 and 15 on 28-day cycles.

Patients had blood samples collected prior to initiation of Ibrutinib, day 1 of cycle 1, day 8 of cycle 1, day 1 of cycle 2, and at the time of disease progression.
From these specimens, researchers have measured circulating MDSC levels, other circulating immune subsets, T cell proliferation, and cytokines / chemokines levels.
Circulating MDSC levels were measured by mass spectrometry.
T cell function was evaluated by CFSE to monitor proliferating cells by dye dilution and cytokine / chemokine levels were measured with a U-PLEX assay.

An increase in circulating MDSC ( 22% to 28%; SD 9.158 ) levels was observed following 7 days of single-agent Ibrutinib compared to baseline.
However, in combination therapy, MDSC levels decreased ( 19%; SD 13.17 ) prior to cycle 2.
Despite increasing levels of circulating MDSC, T cell function improved throughout the study.

Furthermore, plasma levels of chemokines associated with MDSC recruitment and migration significantly decreased with Ibrutinib treatment ( IL-12, CCL2, CCL3, and CCL4 ).

Of the 16 patients, four achieved a partial response and four achieved stable disease. Median progression free survival was 3.5 months and median overall survival was 11.5 months.

In conclusion, the combination of Ibrutinib and Nivolumab was well tolerated, has demonstrated early signs of immune modulation, and has shown preliminary signs of promising clinical activity in patients with metastatic solid tumors. ( Xagena )

Source: American Society of Clinical Oncology ( ASCO ) Virtual Meeting, 2020