During the drug development process, it’s important to characterize the nature and magnitude of any adverse effects a drug may have on cognition, even if the underlying disease is not brain-related. However, many Phase 1 and Phase 2 clinical trials do not incorporate objective, performance-based cognitive measurement tools as part of their safety assessment. Cognitive safety, including the ability to perceive, store and process information, has become a requirement by regulators for many studies and an important consideration of the general public when evaluating medication options.
In a recent phase 2 study of Lorlatinib, a third-generation drug used for ALK-positive advanced non-small-cell lung cancer, a battery of computerized cognitive tests from Cogstate was utilized to detect any potential changes in cognition during 21-day treatment cycles. In the study published in The Lancet – Oncology, Lorlatinib was found to be “an effective treatment option for patients with ALK-positive non-small-cell lung cancer in first-line or subsequent therapy”, and there was “little evidence of true systematic decline in cognition associated with lorlatinib treatment”.
For patients, this is an important result, as lung cancer is the leading cause of cancer death worldwide and non-small-cell lung cancer accounts for about 85% of lung cancer cases and remains difficult to treat, particularly in the metastatic setting, according to a press release from Pfizer, the sponsor of the research.
To assess cognitive function in the study participants, a well-validated 5-part Cogstate test battery was administered via laptop computer, taking about 15-20 minutes to complete. The battery included:
- The International Shopping List task (a measure of verbal learning using a list-learning paradigm), as well as a delayed recall condition requiring the participant to recall the words from the list 15-30 minutes later without having the list read again
- The Detection task (a measure of psychomotor function using a well-validated simple reaction time paradigm with playing card stimuli)
- The Identification task (a measure of visual attention using a well-validated choice reaction time paradigm with playing card stimuli)
- The One Back task (a measure of working memory using a well-validated n-back paradigm with playing card stimuli)
In addition, assessments of mood, using the Beck Depression Inventory-II (BDI-II) scale, and suicidal ideation, using the Columbia Suicide Severity Rating Scale (C-SSRS), were also administered.
While there was evidence of systematic decline in attention observed within several of the cohort subpopulations, true drug-related cognitive decline would manifest on more than one aspect of cognition in the same subpopulation. Therefore, the researchers concluded there was no strong evidence that Lorlatinib was associated with cognitive decline.
Delivering improved treatment options free of adverse cognitive side effects is a promising step forward with the potential to benefit patients battling ALK-positive advanced non-small-cell lung cancer.