Standard dose alectinib versus Therapeutic Drug Monitoring guided alectinib dosing

Currently, over 40% of all recently approved oncolytics are oral agents.1 Compared with the more traditional intravenous therapies, these oral agents are less invasive and more patient friendly. On the other hand, due to home administration, patient’s adherence could be compromised.2 Secondly, the oral administration route makes these agents more prone to drug-drug and drug-food interactions, both resulting in suboptimal drug exposure, with rates varying between only 30% and 70% of desired drug exposure targets.3 Notably, overdosing causes unnecessary and preventable side effects, while underdosing results in reduced effects and tumour growth.
In lung cancer patients treatment with EGFR-TKI has been shown to be influenced by e.g. body weight and renal impairment. Adapting the EGFR-TKI dose could help in preventing major side effects and improve outcome of the treatment4. For ALK-TKI this has not been studied largely yet.
Despite the relative short treatment period of on average a year, and the severity of the disease, still 20% of lung cancer patients have suboptimal adherence.5 This may partly help to explain why survival of patients with metastatic non-small cell lung carcinoma (NSCLC) in real-world daily practice is nearly one quarter shorter than for patients included in clinical trials.6 Adherence is the single most modifiable risk factor that comprises treatment outcomes but is difficult to measure and no studies so far have employed objective methods. Objective, long-term adherence data can support patients’ self-management in the outpatient setting, allows enhanced physician clinical decision making and informs therapeutic drug monitoring (TDM) targets (dose increase or decrease).
Alectinib is used in first and second line settings in ALK positive advanced lung cancer as standard of care.7 Groenland et al. found in an exposure-response analysis of alectinib a median alectinib Cmin of 517 ng/mL (range: 141-1944 ng/mL), with an interindividual variability of 57%. In total, 37% of the patients had a median Cmin< 435 ng/mL. The median PFS was 12.8 months vs. not estimated (95%CI: 19.8 months – not estimated) for patients with Cmin below or above 435 ng/mL, respectively (p=0.04, log-rank) (Figure 1). Multivariable analysis corrected for WHO performance status and prior treatment with ALK-inhibitor(s) resulted in hazard ratio of 4.29 (95%CI: 1.33-13.90, p=0.015) in favour of patients with higher drug exposure.8
Therefore, patients should have an alectinib Cmin ≥ 435 ng/mL, which could be established by therapeutic drug monitoring (i.e. adjusting the dose based on measured drug concentrations). Taken together, we hypothesize that the PFS will increase by more than 10 months comparing therapeutic drug monitoring (TDM) and increasing the dose of alectinib if the Cmin threshold of 435 ng/mL is not reached and with fixed alectinib dosing.

In lung cancer patients treatment with EGFR-TKI has been shown to be influenced by e.g. body weight and renal impairment. Adapting the EGFR-TKI dose could help in preventing major side effects and improve outcome of the treatment4. For ALK-TKI this has not been studied largely yet.

at regular visits (4,8 and every 8 weeks thereafter)

ECG, bloodsampling, scans, optional biopsy