Media release

From: La Trobe University

New results from a multicentre clinical trial show that combining immunotherapy drugs nivolumab and ipilimumab significantly improves treatment response in patients with advanced and difficult-to-treat cancers.

Healthy cells can normally repair errors in their DNA. In mismatch repair-deficient (dMMR) cells, DNA errors are not fixed and genetic mutations accumulate, in a state called microsatellite instability (MSI-H). This can lead to the development of cancers, commonly in the uterus, colon and stomach, and in other organ systems less frequently.

These cancers often present in advanced stages due to their genomic instability and respond poorly to chemotherapy. Therefore, patients have a poorer outcome compared to those with mismatch repair proficient cancers.

The MoST-CIRCUIT trial is conducted across 17 hospitals in Australia and New Zealand and is the first in the world to explore whether combining two immunotherapies can enhance treatment response in non-colorectal dMMR/MSI-H cancers.

The trial is sponsored by the Olivia Newton-John Cancer Research Institute (ONJCRI), which is affiliated with La Trobe University as the School of Cancer Medicine.

Strikingly, the trial achieved an objective response rate (ORR) of 63%, or the percentage of patients whose cancer shrank or disappeared in response to treatment, and 71% of patients showed no tumour progression six months after treatment, affirming that responses to treatment were long-lasting.

In contrast, single-agent immunotherapy (monotherapy) has shown durable benefit in about only one-third of patients with dMMR/MSI-H cancers.¹

Lead investigator A/Prof Oliver Klein, Clinician-Scientist at ONJCRI, says the results mark a major advance for patients with rare cancers.

“This is the first study to demonstrate that this combination treatment can further improve the outcome of these biologically aggressive cancers compared to monotherapy,” says A/Prof Klein.

“Close to two-thirds of trial participants’ cancers responded to treatment, and given the quality and durability of these responses, many of these patients are likely cured of their cancer despite having had metastatic disease.”

These results are timely, coming as the Pharmaceutical Benefits Advisory Committee (PBAC) has recommended tumour-agnostic access to nivolumab and ipilimumab for advanced cancers, including rare malignancies, with Pharmaceutical Benefits Scheme (PBS) listing pending approval.²

The global prevalence of dMMR/MSI-H mutations across solid tumour types is approximately 2.9%.³ Although these cancers are rare, they account for thousands of difficult-to-treat tumours diagnosed across Australia each year, and thousands of patients who urgently need better treatment options.

“There is a significant equity gap for people diagnosed with rare and less common cancers in Australia, driven largely by limited research and knowledge. Too often, that leads to life-limiting outcomes,” says Christine Cockburn, CEO at Rare Cancers Australia.

“Clinical trials are critical for people with rare cancers. The results of this study show the enormous potential of precision oncology and immunotherapy for people with rare cancers. This new research offers hope for cancer patients across Australia with a dMMR/MSI-H mutation – hope that may otherwise have been in short supply.

“We are at a pivotal moment in rare cancer care. With more studies like this, and the Government considering a tumour-agnostic PBS listing for nivolumab and ipilimumab, we are on the cusp of real change that would give more patients a fair chance at life beyond cancer,” Ms Cockburn concludes.

The trial results have been pre-published in JAMA Oncology, accompanied by a commentary emphasising the significance of the findings.