Research

Predicting response to checkpoint inhibitors requires more than a crystal ball

Thursday, 19 Oct 2017


Routine blood tests such as leucocyte counts and lactate dehydrogenase (LDH) along with clinical markers such as adverse events may play a role in predicting response and toxicity to immune checkpoint inhibitors (ICIs).

However most of the evidence is currently restricted to ipilimumab in the treatment of advanced melanoma and more research is required as the number of checkpoint inhibitors expands across a range of cancer types.

The limbic asked Dr Ashley Hopkins, a postdoctoral fellow in the Flinders Centre for Innovation in Cancer, about a recent review of the literature.

Routine blood tests offer ease of use over novel biological markers but are we expecting too much of these simple measures given the ‘complexity of the tumour environment and immune function’?

We should be moving towards the adoption of precision medicines techniques that appreciate the wealth of available information for an individual rather than a dichotomous use of a single marker.

Dr Ash Hopkins

Dr Ash Hopkins

Lymphocyte counts, neutrophil to lymphocyte ratios, and other leukocyte sub-types are promising blood markers which have been associated with response to ICI therapy across multiple studies.

They are also routinely collected and thus can be easily integrated into clinical decision-making for nominal expense.

It is unlikely that they alone will clinically predict response to ICI therapy in all cases, however the exploration of novel biological markers has also been largely underwhelming.

If a novel biological marker is identified it should be appreciated for its additional predictive performance over routinely available data.

LDH levels appear to have an inverse relationship with survival in a number of studies. Can this information be used to personalise treatment and optimise patient outcomes?

More generally elevated LDH levels are a prognostic factor for poor survival outcomes in patients with metastatic melanoma, mRCC and many other tumour types.

Several studies have shown that this effect is similarly consistent in cancer patients treated with immunotherapies.

Without head to head data demonstrating response/survival differences between treatment options for patients with high or low LDH levels it will be difficult to optimise therapy based upon this marker alone.

So while such investigations are conducted, the current level of data could be implemented into prognostic tools or applications to provide realistic expectations of therapy for the patients and clinicians.

Immune-related adverse events may also predict response to treatment and survival. Where is the strongest evidence to date?

To date the association between immune-related adverse events (irAEs) and response/survival with ICI therapies has been minimally investigated, while the studies that have been conducted are small and the findings inconsistent.

As an example, Weber et al pooled data from four studies including two phase III trials to acquire data from 576 advanced melanoma patients treated with nivolumab.

In this study, treatment-related adverse effects of any grade were associated with higher ORR but no progression-free survival benefit. Thus using irAEs to predict response to ICI therapy is an emerging field but requires significantly more research at this stage.

We also need to be able to predict who is most at risk of severe toxicity with checkpoint inhibitors. What baseline tests have shown some utility?

Family history of autoimmune diseases, tumour infiltration, tumour location, previous viral infections, and the concomitant use of medicines have all been proposed, however their investigation for an association with ICI toxicity and irAEs have been minimal.

Similarly, routinely available blood markers have not been investigated. This is an important area of research that should be address in the future.

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