Gut microbiome and cancer: insights from the PRIMMO trial

Managing persistent, recurrent, or metastatic cervical (CC) and endometrial cancer (EC) has long been a major challenge. Many patients are not eligible for curative surgery or radiotherapy, and even modern treatments like immune checkpoint inhibitors (ICIs) have initially shown only limited success.

The search for more effective combination therapies

To improve patient outcomes, researchers worldwide started exploring ICI-based combination therapies. While these approaches showed promise, they often came with increased toxicity, limiting their widespread use. In response, the PRIMMO trial was launched in 2017 to find a more balanced approach: enhancing the immune system’s ability to fight cancer while keeping side effects and costs manageable.

Funded by the Anticancer Fund, Kom op tegen Kanker and the players of the National Lottery (Belgium), the trial aimed to enhance treatment through a combination of seven therapies that, together, would aggressively attack the tumour.

What was the PRIMMO trial?

The PRIMMO trial tested a unique approach by combining:

Pembrolizumab, an ICI that helps the immune system recognize and attack cancer cells.
Localized radiotherapy, used to intensify immune activation.
An immunomodulatory cocktail of five commonly available drugs: cyclophosphamide, aspirin, lansoprazole, vitamin D, and curcumin, to reduce immune suppression and boost T-cell activity.

This innovative strategy sought to counteract the tumour’s ability to evade the immune system, potentially improving patient outcomes with ICIs.

Did it work?

The results showed best overall response rates between 11% and 22%, falling short of expectations for widespread success. As a result, the trial was considered negative. However, some patients experienced long-lasting responses, even in cases that were otherwise difficult to treat. Unfortunately, gastrointestinal toxicity was higher than anticipated, highlighting the challenge of balancing efficacy with toxicity/tolerability. Hence, no confirmatory phase 3 trial will be initiated.

A breakthrough in gut microbiome research

Another innovative aspect of the PRIMMO trial was its exploratory study on the gut microbiome. By analysing faecal samples, researchers investigated the potential impact of gut bacteria on ICI therapy. This was the first study to explore this connection in cervical and endometrial cancer patients, and its findings, recently published in the scientific journal Gynecologic Oncology, revealed key insights:

Certain gut bacteria that produce short-chain fatty acids (e.g. Blautia) were more prevalent in patients with good therapeutic outcomes.
Conversely, other bacteria were linked with poorer outcomes and some even with treatment-related adverse events.
Patients could be classified into two categories based on their gut microbiome before starting treatment. One group had a fourfold lower risk of death than the other.

These findings suggest that the gut microbiome may play a crucial role in balancing treatment efficacy and toxicity, potentially paving the way for future therapeutic and prognostic strategies.

What’s next?

Final publications from the PRIMMO trial are expected to be released later this year. These will include additional findings on a third gynaecologic cancer type _uterine sarcoma_ along with new insights from translational research.

Since the PRIMMO trial, multiple larger phase 3 trials have confirmed the benefit of ICI-based therapies in specific CC and EC patient subgroups, leading to several new drug approvals and reimbursements. Meanwhile, ongoing research continues to refine and enhance the management of gynaecologic cancers, with antibody-drug conjugates emerging as particularly promising therapeutics.

The PRIMMO trial highlights the Anticancer Fund’s commitment to advancing treatment options for hard-to-treat cancers. By building on past research and exploring innovative treatment avenues, we hope to move closer to achieving more effective, accessible, and less toxic cancer therapies.

Related publications

Trial protocol: https://doi.org/10.1186/s12885-019-5676-3

Trial results:

study 1 https://doi.org/10.1007/s00262-022-03253-x
study 2 https://doi.org/10.1007/s00262-024-03873-5
study 3 https://doi.org/10.1136/ijgc-2022-ESGO.401

Gut microbiome analysis: https://doi.org/10.1016/j.ygyno.2024.10.020

More information about the PRIMMO trial

Emiel De Jaeghere

author

Emiel De Jaeghere graduated as a medical doctor in 2018 from Ghent University, Belgium. With a strong passion for scientific research, he pursued a PhD, supported by the Research Foundation-Flanders, at the Laboratory of Experimental Cancer Research (Ghent University) and the Department of Medical Oncology at Ghent University Hospital. His research, focused on the tumor immune microenvironment, was conducted under the guidance of Prof. Dr. Hannelore Denys, Prof. Dr. Olivier De Wever, and Prof. Dr. Frédéric Amant. Emiel successfully defended his PhD in 2025.
Throughout his training, Emiel developed a specific interest in the treatment of gynecological cancers, including cervical, endometrial, and ovarian cancers, as well as rarer types. To expand his expertise in this field, he completed internships at renowned oncology hospitals, such as Kliniken Essen-Mitte (Essen, Germany), the Institut Jules Bordet (Brussels, Belgium), and Erasmus MC (Rotterdam, The Netherlands).
Emiel De Jaeghere is dedicated to improving outcomes for women with gynecological cancers through high-quality care and research. His work focuses on advancing treatment options and enhancing the clinical management of gynecological cancer.