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Miller et al. J Cancer Metastasis Treat 2019;5:68 I http://dx.doi.org/10.20517/2394-4722.2019.001 Page 7 of 11

IL-1/6 inhibitors
The IL-1 pathway has been previously targeted in humans with the recombinant human IL-1 receptor
antagonist Anakinra and the neutralising monoclonal anti-IL-1 antibody Canakinumab. Anakinra, as
previously discussed, has had success in rheumatoid patients but has yet to be trialled in patients with
[65]
cancer . However, a more specific IL-1a human monoclonal antibody, MABp1, has shown promising
[73]
results in cancer. An initial dose escalation and expansion study was designed using MABp1 . The first
dose escalation study was performed in patients with refractory cancer to assess its safety and tolerability.
It identified an optimal intravenous dose which was then used in the following phase II study of forty-two
[73]
patients . Median plasma IL-6 concentrations decreased from baseline to week 8 (P = 0.08). Of those 30
patients who had an assessment of body composition, lean mass increased significantly by 1.02 ± 2.24 kg
[73]
(P = 0.02) . It was then compared to megestrol acetate in patients with advanced colorectal cancer and
[74]
> 5% weight loss. Those in the MABp1 treatment arm showed a trend towards increased survival . A
placebo-controlled, double blind phase III study in 333 patients with advanced colorectal cancer was then
[75]
undertaken which resulted in increased lean body mass as well as symptom relief (pain, anorexia, fatigue) .

IP1510 is a synthetic peptide IL-1 receptor antagonist. Pre-clinical studies found it to have low toxicity, and
to be a potential effective treatment for cachexia. It was then trialled in advanced gynaecological cancer
patients where it was well tolerated, and it significantly improved patient anorexia, depression and physical
[76]
performance. Weight stabilisation or gain was seen in 17 of the 26 enrolled patients . Interpretation of the
current data is limited because the study was neither randomised nor controlled. However, further larger
[74]
trials are to be initiated targeting IL1 in cancer cachexia .

Studies involving IL-6 antibodies have been undertaken in patients with advanced non-small cell lung
cancer. The humanised monoclonal IL-6 antibody Clazakizumab [ALD518] has shown beneficial results in
increasing haemoglobin levels and preventing loss of lean body mass. Fatigue scores were also improved
[77]
compared with controls . There are, however, no phase III trials underway.
Immunotherapeutic agents continue to be a promising treatment for cancer cachexia and may be added to
the multi-modal management approach for this complex syndrome.

Standard cancer immunotherapy
Anti-cancer immunotherapy including bermekimab above has been shown to improve outcomes in a
range of tumour types, including melanoma, lung and bladder cancers, many of which respond poorly to
traditional agents. Some of these therapies are, however, poorly understood. Patients with cancer cachexia
have been shown to respond poorly to some immunotherapies such as immune check point inhibitor
[78]
therapy, likely due to elevated clearance or the establishment of primary resistance . In two large clinical
trials involving patients with melanoma and non-small cell lung cancer, there was a paradoxical association
between plasma clearance of Pembrolizumab [a programmed cell death protein inhibitor (PD-1)] and
poor overall survival. Those patients who responded poorly were noted to have reduced body weight
and low albumin, suggesting that the presence of cachexia rendered these patients unable to respond to
[76]
Pembrolizumab . The hypoalbumaemia was hypothesised to explain the elevated plasma clearance, and
therefore the dose was increased in these patients to counteract this apparent resistance, but it did not
result in improved outcomes. Studies in lung cancer patients treated with immunotherapy have shown that
decreases in pre-treatment BMI, weight loss and high neutrophil:lymphocyte ratio were associated with
[79]
significantly shorter progression-free survival . However, other studies in lung cancer patients have also
shown that two thirds of those receiving PD-1 and PD-L1 immune check point inhibitors experienced
[80]
stability or an increase in their skeletal muscle index . Thus, although at first glance immunotherapy
would seem to be a natural antidote to cancer cachexia, it is difficult to unravel the clinical impact of
immunotherapy from the known adverse outcomes of any cancer patients with poor nutritional status.