Immunotherapy has transformed the treatment landscape of several cancers. In colorectal cancer, however, its benefits have so far been limited to a small subgroup of patients.

Today, a new Phase III clinical trial—the BATTMAN study—is exploring whether this approach could also benefit patients with microsatellite stable (MSS) metastatic colorectal cancer (mCRC), particularly those without liver metastases.

A story of success… but only for some

Over the past decade, immunotherapy—especially immune checkpoint inhibitors—has shown durable responses in patients with dMMR/MSI-high colorectal cancer.

For these patients, treatments targeting immune checkpoints such as PD-1 have become a standard of care. However, this group represents only a small proportion of cases. The majority of patients—around 95%—have MSS tumours, for which effective immunotherapy options are still limited.

Understanding immune checkpoints: PD-1 and CTLA-4

Immune checkpoints are natural mechanisms that regulate the activity of the immune system.

• PD-1 (Programmed Death-1) is a protein on immune cells that acts as a “brake,” preventing excessive immune activation. Some cancer cells use this pathway to avoid detection. PD-1 inhibitors block this signal, helping the immune system recognise cancer cells.
• CTLA-4 is another checkpoint that works earlier in the immune response. It regulates how strongly immune cells are activated at the initial stage. CTLA-4 inhibitors can enhance this activation, increasing the likelihood that immune cells respond to cancer.

Targeting both pathways at the same time may help generate a stronger and more sustained immune response.

A new approach: combination immunotherapy

The BATTMAN trial evaluates a combination of:

• Botensilimab (a next-generation CTLA-4 inhibitor)
• Balstilimab (a PD-1 inhibitor)

This dual approach is designed to enhance immune activation through complementary mechanisms, with the aim of improving outcomes in MSS tumours.

Encouraging signals from earlier studies

Interest in this strategy is supported by early clinical data presented at major oncology meetings, including ESMO GI, where promising activity was observed in heavily pre-treated MSS mCRC patients—particularly in those without liver metastases.

In addition, the combination has been used in France through compassionate use programmes, allowing selected patients to access the treatment outside clinical trials and contributing to the growing clinical experience with this regimen.

The BATTMAN trial: focusing on a specific MSS population

The BATTMAN study is a randomised Phase III clinical trial focusing on patients with MSS mCRC without liver metastases—a group that may have a more favourable immune environment.

The trial will evaluate whether this combination can improve key outcomes such as survival, disease control and tolerability.

Looking ahead

If successful, the BATTMAN trial could represent an important step towards expanding the role of immunotherapy in colorectal cancer and addressing the needs of patients with MSS disease.

Infobox: Understanding immunotherapy

What is immunotherapy?
A type of treatment that supports the immune system in recognising and responding to cancer cells.

What is PD-1?
A protein on immune cells that acts as a “brake” to prevent excessive immune reactions. Tumours can use this pathway to avoid detection.

What do PD-1 inhibitors do?
They block this signal, helping the immune system better recognise cancer cells.

What is CTLA-4?
Another immune checkpoint that regulates the early activation of immune cells.

What do CTLA-4 inhibitors do?
They enhance the initial activation of immune cells, potentially increasing the overall immune response.

Why combine PD-1 and CTLA-4 inhibitors?
Because they act at different stages of the immune response, combining them may lead to a stronger and more sustained effect.

Why is MSS mCRC challenging?
MSS tumours are generally less responsive to current immunotherapy approaches, which is why new strategies like BATTMAN are being explored.

Author:

Marianna Vitaloni