Adding JAK inhibitors to ICI treatment for patients with refractory lymphoma and NSCL works, paradoxically.
Two papers recently published in Science have shown that combining the use of JAK inhibitors with immune checkpoint inhibitors greatly improves prospects for patients with Hodgkin lymphoma and those with non-small cell lung cancer.
In the Hodgkin lymphoma trial, overall survival was 87% and progression free survival was 46% at two years. This is compared with a known overall survival of 24% and progression free survival of 22% when patients receive only immune checkpoint inhibitors.
The phase 1 trial involved 19 patients with relapsing-refractory Hodgkin lymphoma, mostly stage III-IV. All had previously received immune checkpoint inhibitors and shown either a mixed response or no response.
In this study, all patients were given ruxolitinib, a JAK1 and JAK2 inhibitor, followed by nivolumab, a PD-1 immune checkpoint inhibitor, at day eight and then once every four weeks for two years or until progression.
Six patients had a complete response, four had a partial response, and one had an indeterminate response, with a best overall response of 53%.
“We demonstrate that JAK inhibition is not immune suppressive but rather stimulatory, suggesting that the context of JAK inhibitor usage dictates the ultimate treatment outcome. … [I]t will be important to explore the clinical potential of JAK inhibitors with ICI in solid tumours, particularly those in which suppressive myeloid cells correlate with poor response to ICI monotherapy,” the authors write.
The phase 2 non-small cell lung cancer trial used a combination of JAK1 inhibitor itacitinib and PD-1 immune checkpoint inhibitor pembroluzimab in 21 treatment-naïve patients. These patients had a median progression-free survival of almost two years compared to patients in other trials on immune checkpoint inhibitors alone where median PFS was only 6.5-10.3 months.
The patients received two three-week cycles of pembrolizumab, followed by up to two cycles of pembrolizumab plus itacitinib, and then maintenance on the ICI alone.
“The two papers in Science by Zak et al and Matthew et al are deeply exciting and important for clinicians and patients,” Associate Professor Vivek Naranbhai, immunologist, clinical oncologist and clinician scientist at the School of Translational Medicine, Monash University, told OR.
“This is because a) they describe a new highway for the field to pursue in its journey towards harnessing immunity for more patients and b) they clearly describe the signposts for success by delineating mechanisms by which JAK+ICI combinations may work.
“Whilst it may not have immediate practice changing effects, it will engender a slew of new clinical trial options for patients both in the ICI refractory and first line setting in haematologic and solid cancers.
“For drug developers and immuno-oncologists, the papers help lend credence to additional mechanistic targets that could perhaps surpass JAK-ICI, such as tamping down harmful inflammation and myeloid derived suppressor cells, and enhancing CD8 T-cell plasticity and lymphocyte proliferation.”
Translating research on immune checkpoint therapy enhancement into clinical success has not proven an easy task, said Professor Naranbhai.
“Trying to find combination therapies has been a big effort. People have spent billions of dollars and 10s of 1000s of hours trying different approaches, including in clinical trials. It hasn’t yet really yielded much excitement,” he said.
“We don’t know if this will really work. But I think what’s encouraging is you’ve got two different diseases, with mechanism underlying [the findings].
“And that’s the key thing for me, that there’s mechanism paired with actual human clinical data. That’s most compelling because when you validate the target, and you understand the mechanism, typically we know from previous drug discovery that that increases the odds of success markedly.”
Professor Naranbhai said the studies themselves were “revolution-making” and “in the vein of new types of papers where people are essentially doing more rapid translation of discovery”.
“For example, in the Hodgkin lymphoma paper, they do a series of mouse experiments, they discover something, they do the human experiments, and then in the human experiments, they go on to discover the mechanism and tie it back together,” he said.
“They’ve done a tremendous job.”
