Publish date: 26 August 2022

A study at UCLH has found a combination treatment of immunotherapy with an experimental drug may reverse a cancer’s resistance to immunotherapy – making the cancer sensitive to treatment again.

Results published in the Journal for Immunotherapy of Cancer showed that overall, 37% of cancer patients enrolled in the trial had their disease kept in check for 24-weeks or more after receiving the immunotherapy drug pembrolizumab alongside the experimental drug guadecitabine.

This combination treatment could be a new option for patients with lung cancer and other tumours whose cancer has progressed and resisted immunotherapy.

Pembrolizumab is a drug that has been successful at treating a range of solid tumours. However, cancers can develop resistance to pembrolizumab and some patients who initially benefit from the drug will eventually see their disease progress.

Guadecitabine may be able to help overcome this resistance, by preventing cancer’s ability to suppress the immune system and evade immunotherapy.

Clinical research at UCLH and The Institute of Cancer Research, London, and The Royal Marsden NHS Foundation Trust aimed to investigate whether guadecitabine had the potential to overcome resistance to pembrolizumab in a combination approach and establish the dose and side effects of this treatment.

The study over three years used a combination of guadecitabine and pembrolizumab to treat 34 patients with cancer that included those with lung, breast and prostate cancer, 30 of whom had their cancer analysed for immune activity and cancer growth.

Guadecitabine was supplied by Astex Pharmaceuticals, Inc. and the study received funding from MSD, with support from a grant from Cancer Research UK and the Experimental Cancer Medicine Centre Initiative.

Of the 30 patients who had their cancer activity analysed, 37 per cent had their disease controlled and did not see it worsen for 24 or more weeks from the guadecitabine-pembrolizumab combination.

60 per cent of the cohort had previously received immunotherapy, 47% of whom had seen their cancer progress after treatment. After the combination treatment, 39% of patients’ cancer did not get worse after 24 weeks – highlighting the potential of this approach.

The combination treatment seemed to be particularly beneficial for non-small cell lung cancer NSCLC; 42% had their disease controlled for 24 weeks or more, including patients whose cancer had previously progressed on immunotherapy – a sign that the immune system may be being restimulated against the tumour. In addition, the study established a safe dosage of guadecitabine with pembrolizumab and found that the treatment had tolerable side effects.

Consultant medical oncologist Dr Dionysis Papadatos-Pastos, who led the UCLH portion of the trial, said: “Immunotherapy is an exciting treatment but unfortunately some patients do not respond to it or their cancers have found a way to evade it. If we can use this combination approach to re-sensitise some patients’ cancers to immunotherapy, that will be hugely beneficial to patients. Larger studies are now needed but we are encouraged by these initial results.”