Exclusive: UK trial finds finds combination of drugs can work where tumours have become resistant to immunotherapy
A new cancer treatment can stop the disease advancing in patients who are resistant to immunotherapy, doctors have discovered.
Immunotherapy uses the immune system to target and kill cancer cells, and can save lives when other treatment options, such as surgery, radiotherapy or chemotherapy, have failed. However, it cannot help all patients, and some tumours can evolve to resist it.
Now oncologists in the UK have found a two-pronged treatment – immunotherapy combined with guadecitabine, a novel experimental drug – can reverse a cancer’s resistance to immunotherapy. Patients expected to die after exhausting all treatment options survived much longer, they found.
The combination of pembrolizumab, an immunotherapy drug, and guadecitabine, a next-generation DNA hypomethylating agent, halted the advance of cancer in more than a third of patients enrolled in the early phase 1 trial. The results are published in the Journal for ImmunoTherapy of Cancer.
The dual combination could become an effective new weapon against several forms of cancer, experts at the Institute of Cancer Research and Royal Marsden NHS foundation trust said.
Patients in the trial, from the Royal Marsden and University College London hospital, included those with lung, breast, prostate and bowel cancer.
“I think one of the most important things about this trial is that we used multiple different methods to look for changes in the immune system, robustly showing that it was being influenced by the combination treatment,” the study’s chief investigator, Prof Johann de Bono, said.
De Bono, a professor of experimental cancer medicine at the Institute of Cancer Research and a consultant medical oncologist at the Royal Marsden, added: “In the long term we hope that if these effects are confirmed in other patient groups and future studies, guadecitabine and pembrolizumab could help to tackle some of the resistance to immunotherapy we see in too many types of cancer.”
The study used pembrolizumab and guadecitabine to treat 34 cancer patients, 30 of whom had their tumours analysed for immune activity and cancer growth. Every three weeks for three years, they had an injection of guadecitabine for four days in a row – and pembrolizumab on the first of those days.
Pembrolizumab is an immune checkpoint inhibitor drug that has already proved successful in treating a range of cancers, including lung and skin cancers. However, tumours can develop resistance to it and some patients who initially benefit will eventually get sicker.
The study lead, Dr Anna Minchom, a clinical scientist at the Institute of Cancer Research and a consultant medical oncologist at the Royal Marsden, said: “Immunotherapy has shown amazing promise in cancer care over the last decade, but it doesn’t work well in all cancers and cancers can often become resistant. This combination might be a way to target their cancer even after it has stopped responding to immunotherapy.”
Guadecitabine may help overcome this resistance, doctors, researchers and scientists involved in the trial have discovered.
Of the 30 patients whose cancer activity was analysed, for 37% the disease was stopped in its tracks, with no tumour progression for 24 weeks or more. Three-fifths of the group (60%) were resistant to immunotherapy before the trial. Of those, almost four in 10 (39%) did not get any sicker after taking the drug combination.
The new treatment seems particularly beneficial for lung cancer patients. Of those resistant to immunotherapy, half had their disease controlled for 24 weeks or more.
Alison Sowden, 61, from Dorset, was diagnosed with lung cancer four years ago and told she had a year to live, but then received pembrolizumab for three years. She is now free of cancer.
“I know there is a chance that my cancer may come back and develop resistance to treatment, so it is reassuring to know research efforts aiming to reverse cancer’s resistance to immunotherapy are under way,” she said. “I hope this new experimental drug combination will eventually make it to the clinic and help people who have developed resistance to pembrolizumab.”