ASCO 2018: is LAG-3 the next checkpoint target?

8 June 2018 (Last Updated June 8th, 2018 11:49)

On June 4 at this year’s American Society of Clinical Oncology (ASCO) annual meeting, Novartis reported dose escalation results from its Phase I/II study of anti-LAG-3 monoclonal antibody LAG525 with or without its anti-PD-1 inhibitor spartalizumab in advanced malignancies. The treated patients included those who had progressed on, or were intolerant to, standard therapy, or for whom no standard therapy exists.

ASCO 2018: is LAG-3 the next checkpoint target?

At this year’s American Society of Clinical Oncology (ASCO) annual meeting on 4 June, Novartis reported dose escalation results from its Phase I/II study of anti-LAG-3 monoclonal antibody LAG525 with or without its anti-PD-1 inhibitor spartalizumab in advanced malignancies. The treated patients included those who had progressed on, or were intolerant to, standard therapy, or for whom no standard therapy exists.

LAG525 blocks binding of LAG-3, a negative regulator of T-cell signalling, to MHC class II on tumour cells, which renders the tumour microenvironment less immunosuppressive, and may therefore enhance the activity of PD-1 blockade. Preclinical studies have shown synergistic anti-tumour activity when blocking PD-1 and LAG-3 together, which Novartis is now aiming to demonstrate in the clinic.

Responses among 121 treated patients were seen with the combination therapy, but not with LAG525 alone, including one complete response and 11 partial responses. While this looks promising at first glance, importantly, it was not possible to determine from this early phase dose escalation study if those patients would have responded to PD-1 blockade alone, so the contribution of LAG525 is unclear.

Also of note, while the study showed infiltrating immune cells in the tumour at the start of cycle three, no assessment of correlation with response was presented. In triple-negative breast cancer tumour biopsies, a trend in conversion of immune-cold to immune-activated biomarker profiles was also seen, adding weight to the proof of concept for this combination.

Novartis has succeeded in showing that the combination is safe, and has early signs of efficacy. However, this is early data, and must therefore be viewed with caution. Although responses have been seen in refractory tumour types, many patients still did not respond, and so Novartis still has work to do to identify the precise cohort of patients for whom this combination could have clinical utility. Biomarker analysis of these data could also be used in order to understand the mechanisms of resistance to prior regimens, and to which therapies these patients may subsequently respond.

Amongst the many combination studies presented at ASCO this year, these data show promise, but the community understandably remains cautious until later stage data in a larger, more defined cohort is available.

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