Background
In advanced nonsquamous non–small cell lung cancer (NSCLC), small molecule kinase inhibitors (SMKIs) have become a keystone treatment.1–3 Alectinib is a second-generation SMKI registered as the first-line treatment for patients with altered anaplastic lymphoma kinase–positive (ALK+) advanced NSCLC.4 This type of alteration is present in up to 5% of patients with NSCLC.5 Alectinib has shown to be a highly effective and safe treatment in ALK+ NSCLC, with a response rate of 83% and a median progression-free survival (PFS) of 35 months.1,6,7
The effectiveness of alectinib treatment is associated with its exposure.8,9 According to the FDA’s pharmacokinetic report,9 patients with an alectinib exposure <435 ng/mL had less tumor size reduction than those with an alectinib exposure >435 ng/mL. This exposure–response threshold was confirmed in a recent clinical study.8 Patients who had an alectinib trough plasma concentration (Ctrough) above the threshold had a 2-fold increased PFS compared with patients with a lower alectinib exposure.8 The 37% of patients who did not reach this threshold had a relatively poor PFS of only 12.8 months.8 Currently, alectinib concentrations are only measured for research purposes and not (yet) used in clinical practice, although increasing evidence shows the usefulness of dosing based on drug concentrations.10,11
Alectinib has low aqueous solubility, and therefore its gastrointestinal absorption is poor.12,13 Hence, alectinib’s bioavailability is limited to 37%.12 In addition, this results in a high intrapatient and interpatient variability in exposure.9 Therefore, knowledge of the factors that influence the absorption of alectinib is crucial to improve treatment efficacy.
Absorption of alectinib is largely influenced by food. In healthy subjects, a single administration with a high-fat meal versus administration in a fasted state resulted in a 3-fold increase in exposure.14 Hence, patients are recommended to take alectinib with a meal.4 However, the precise relationship between food intake and the absorption of alectinib is currently unknown. Hypothetically, this interaction could solely be a food effect, depending on whether alectinib is administered with food. However, a fat–exposure relationship is more likely, because the effect of a high-fat meal on the total and peak exposure was quite substantial.14 Fat could increase the solubility of a lipophilic substance such as alectinib in the gastrointestinal tract. Nonetheless, the relationship between absorption and fat intake has never been studied.15 In addition, the effect of a (low-fat) continental meal on exposure is unknown.
Although alectinib has mostly mild toxic effects, (extreme) weight gain is an important side effect in 10% of patients treated with alectinib.7 A low-fat diet could be proposed to overcome this weight gain; however, this may impair treatment efficacy. Furthermore, it is likely that patients tend to eat more (fat) for lunch than for breakfast. If patients are not able to consume breakfast in the morning, intake with lunch could be an alternative.
Therefore, in this study, we investigated alectinib exposure when it was administered with a continental breakfast and whether intake with low-fat yogurt or a self-chosen lunch could be an alternative.
Patients and Methods
Patient Eligibility
Adult patients treated with alectinib for advanced ALK+ NSCLC at Erasmus University Medical Center were eligible to participate when they were on alectinib treatment for at least 2 weeks (to guarantee steady-state plasma concentrations), had a maximum ECOG performance score16 of 2 points, were willing to adhere to dietary restrictions, did not have known comorbidities that could impair drug absorption (eg, gastrectomy/enterectomy, achlorhydria), and did not use drugs or supplements that could potentially interact with alectinib and therefore alter plasma concentrations (eg, CYP3A4 modifiers). All eligible patients had to provide written informed consent to participate in the trial. The local ethics committee of the Erasmus University Medical Center Rotterdam approved the trial (MEC 21-0478), and the trial was registered in the Dutch Trial Registry (https://trialsearch.who.int/; NL9702). The study was conducted in accordance with good clinical practice and the Declaration of Helsinki.17,18
Study Design
This trial was performed as a single center, open-label, randomized crossover trial, with 3 study periods (Figure 1). Patients were randomized after registration, with a 1:1 allocation ratio, to either treatment sequence “A–B–C” or “C–B–A.”
Study design of the randomized crossover pharmacokinetic DIALECT trial.
Abbreviations: A, continental breakfast; B, low-fat yogurt; C, self-chosen lunch; PK, pharmacokinetic (Ctrough).
Citation: Journal of the National Comprehensive Cancer Network 21, 6; 10.6004/jnccn.2023.7017
Patients were instructed to take alectinib with different diets for 3 periods of 7 days each, because a new steady-state is formed within 7 days.9 The first dose was taken with either (A) a continental breakfast (2 slices of wheat bread with butter and either ham, cheese, or peanut butter, and 250 mL of semi-skimmed milk) at 8 am; (B) 250 g of low-fat yogurt (semi-skimmed; 1.5% fat) and 250 mL of water at 8 am; or (C) a self-chosen lunch at 12 pm. The second dose was taken with a self-chosen dinner at 7 pm. Two days prior to pharmacokinetic sampling, patients were instructed to consume a low-fat dinner (eg, no portions of meat/fish, fries) and these dinners had to be identical in each period because they were considered to be an important influencing factor. Prior to administration of a new alectinib dose in the morning of day 8 of each trial period, a blood sample was drawn for pharmacokinetics. The blood samples were centrifuged within 24 hours at 2,500 g for 10 minutes, and plasma was stored at −80°C until measurement. Alectinib plasma concentrations were measured using validated ultraperformance liquid chromatography–tandem mass spectrometry methods, with an accuracy ranging from 96.9% to 99.6%.19 Further details regarding the analytical performances are provided by Veerman et al.19
Toxicity
Patients were provided with diaries to assess toxicity per study period. The incidence of toxicity was corrected for preexisting toxicity at baseline. Severity of toxicity was graded following the NCI CTCAE, version 5.0.20
Fat Content
The fat content of the continental breakfast and the low-fat yogurt diet was determined in advance by a dietician because a standard diet was prescribed (see supplemental eTables 1 and 2, available with this article at JNCCN.org). For the self-chosen lunch, the fat content was studied afterward with detailed data from the patient diaries. The fat content of the regularly taken breakfast was calculated based on a questionnaire at baseline. The content of fat was calculated with a standardized macronutrients calculator, which accounts for the preparation method and is used in daily practice by dieticians. This tool is provided by the Netherlands Nutrition Centre, based on an independent database developed in collaboration with the National Institute for Public Health and the Environment.21
Pharmacokinetic Analysis
Alectinib is cleared from plasma by first-order elimination.22 To calculate trough levels at the equal time points, plasma concentrations were extrapolated to make a robust comparison.23 Levels were calculated to exactly 12 hours after the last administration (just before the subsequent dose), because this indicates alectinib trough levels that account for twice-a-day administration. These calculations were performed using a population half-life of 33 hours.4
Study Endpoints and Statistical Analyses
The primary endpoint was to compare the relative difference in alectinib plasma concentrations 12 hours after last intake (Ctrough) between the 3 study periods. A pharmacokinetic effect is considered clinically relevant if the relative difference in Ctrough is at least −20% or +25%.24 We considered a within-patient standard deviation of 0.25. This required 20 patients to detect a significant difference with 80% power and a 2-sided significance level of 0.05, including a Bonferroni correction because 3 comparisons were made. Because pharmacokinetic data are often positively skewed,25 a log-transformation was applied. (Log) plasma Ctrough concentrations were compared between different diets using linear mixed modeling. Mean relative differences including 95% CIs were obtained and exponentiated to provide geometric mean ratios with 95% CIs. Treatment, sequence of treatment, and treatment period were modeled as fixed variables, whereas the subject within sequence was modeled as a random effect. Variance of the pharmacokinetic data was estimated using restricted maximum likelihood (REML), and the Kenward-Roger method26 was used for computing the degrees of freedom.
Secondary endpoints were the incidence and severity of toxicity, reaching the efficacy threshold, and fat content of the diets throughout the periods. Incidence of toxicity and reaching the efficacy threshold were assessed per period, and differences were tested using a Cochran’s Q test. Fat intake with a self-chosen lunch was averaged per day per patient in this period. The difference of fat content in the regularly taken breakfast compared with the self-chosen lunch was tested with a paired t test. The differences between fat content of the regular breakfast versus low-fat yogurt and of the continental breakfast versus the self-chosen lunch were tested with a one-sample t test.
Results
Trial Population
Between August 2021 and April 2022, a total of 23 patients were sequentially included and randomized. Of these patients, 3 dropped out after randomization due to switching SMKI therapy, withdrawal of participation due to personal circumstances, and impaired absorption due to an enterectomy. Baseline characteristics of the 20 evaluable patients are presented in Table 1.
Demographics of Analyzed Patients
Pharmacokinetic Effects of Diets
Geometric mean alectinib Ctrough levels of 607 ng/mL were observed with diet A (continental breakfast), 516 ng/mL with diet B (low-fat yogurt), and 645 ng/mL with diet C (self-chosen lunch). Linear mixed modeling showed a 14% (95% CI, −23 to −5; P=.009) and 20% (95% CI, −25 to −14; P<.001) lower Ctrough when administered with low-fat yogurt compared with a continental breakfast and self-chosen lunch, respectively. Administration with a self-chosen lunch did not statistically change the alectinib exposure compared with administration with a continental breakfast (+7%; 95% CI, −2 to +17; P=.243). Furthermore, a higher coefficient of variation of 39% was seen in the low-fat yogurt period, compared with 30% in the continental breakfast and 35% in the self-chosen lunch period. The median extrapolation of the concentration to 12 hours after intake was 116 minutes (range, −115 to 180 minutes). All pharmacokinetic parameters are depicted in Table 2 and Figure 2A.
Pharmacokinetic (Ctrough) Effects and Fat Content of Different Diets During Alectinib Treatment
Pharmacokinetic effect of the studied diets. (A) Geometric means of alectinib exposure (Ctrough) with standard deviations. (B) Individual alectinib levels (Ctrough). Efficacy threshold = 435 ng/mL.
Abbreviations: diet A, continental breakfast; diet B, low-fat yogurt; diet C, self-chosen lunch; NS, not significant.
**P≤.01; ***P≤.001.
Citation: Journal of the National Comprehensive Cancer Network 21, 6; 10.6004/jnccn.2023.7017
In Figure 2B, the Ctrough levels of every individual patient are presented per studied diet. For diets A and C, all but 1 of the patients (5%) were above the efficacy threshold of 435 ng/mL. With diet B, 7 patients (35%) were below the threshold. These proportions differ significantly (P=.002). In addition, the individual effects were mostly similar across patients. Ctrough was always lower with the low-fat yogurt diet than with the continental breakfast and/or the self-chosen lunch.
In a subgroup analysis to evaluate the influence of dose to the magnitude of the food effect, no substantial difference between subgroups was seen. This was tested as ≤450 mg twice daily versus 600 mg twice daily because there was a lack of power in the 300 mg twice-daily group, which consisted of just 2 patients.
Toxicity
The incidence of adverse events (AEs) with each studied diet is depicted in Table 3. Overall, the incidence of AEs was low, with 9 (45%) AEs during the continental breakfast diet, 7 (35%) during the low-fat yogurt diet, and 5 (25%) during the self-chosen lunch diet. This was not statistically different across diets (P>.05). Most AEs were grade 1 (89%). With both the low-fat yogurt diet and the self-chosen lunch diet, 1 grade 2 event was reported. No serious AEs were reported.
Incidence of Adverse Events With Studied Diets
Fat Content
The absolute fat content between diets differed. The mean fat content was 21.3 g with the continental breakfast diet, 3.8 g with the low-fat yogurt diet, and 19.5 g with the self-chosen lunch diet (interquartile range, 16.2–22.5 g). The regularly taken breakfast reported at baseline contained 11.1 g of fat (interquartile range, 6.2–14.0 g). This was significantly lower (P<.001) compared with the self-chosen lunch and significantly higher (P<.001) compared with the low-fat yogurt. The fat content in the self-chosen lunch was not statistically different from the continental breakfast (P=.21).
Discussion
This is the first study to describe an interaction of food with different fat percentages in combination with alectinib. In this study, a clinically relevant food–drug interaction (FDI) was found when alectinib was administered with low-fat yogurt. Patients and physicians should be aware of this potentially dangerous FDI, because this could hamper treatment efficacy. Alectinib intake with a self-chosen lunch resulted in similar drug exposure compared with a continental breakfast. Hence, a self-chosen lunch could be a safe and patient-friendly alternative for alectinib intake with a continental breakfast.
Significant decreases in exposure of 14% and 20% were seen when alectinib was administered with low-fat yogurt in comparison with a continental breakfast and self-chosen lunch, respectively. Because the exposure of alectinib is correlated with the length of PFS, patients and physicians should be aware of the risk for suboptimal treatment when alectinib is taken with low-fat yogurt. We especially warn patients with known Ctrough levels close to or below 435 ng/mL because they are at risk for subtherapeutic exposure and subsequent treatment failure. In this study, we only studied the exposure of alectinib when taken with a low-fat yogurt as a low-fat diet. However, we think it is probable that low exposure will also be found when it is studied with other low-fat diets. Thus, patients should also be cautioned for subtherapeutic exposure with other low-fat breakfasts.
Alectinib administration with a self-chosen lunch did not significantly change exposure compared with administration with a continental breakfast. This is probably because of a similar fat content in the 2 diets. However, in daily life, our patients consumed a breakfast with >40% lower fat content than the predefined continental breakfast. Hence, when alectinib is administered with a self-chosen breakfast, this could also result in a clinically relevant decreased alectinib exposure. Because patients consume almost 2-fold more fat during a self-chosen lunch compared with a self-chosen breakfast, intake with lunch should be advised in particular for patients who are not capable of consuming at least a continental breakfast. For those patients, alectinib intake with lunch is a patient-friendly and effective alternative. For prescribers, it is important to be aware of this option to further optimize alectinib treatment effectiveness, and this underlines the importance of adequate dietary counseling before and during alectinib treatment.
Similar pharmacokinetic effects were seen in a study with ceritinib, also an ALK+ SMKI.27 Intake with a low-fat meal resulted in a 54% increase of ceritinib exposure, whereas a high-fat meal resulted in a 73% increase of ceritinib exposure compared with fasted state.28 Like alectinib, ceritinib is poorly soluble,27 which indicates that a similar relationship with fat intake could exist for ceritinib. Additionally, a higher exposure is observed for pazopanib, nilotinib, and lapatinib when administered with more meals that contained fat.29–31
There are some limitations to address. With this study design, patient adherence to the prescribed interventions was important. Adherence was monitored via a thorough consultation at the start of the study, and via telephone or in-person consultations during the study periods. Compliance was further studied using diaries in which patients reported their daily dietary intake in detail as well as the time of alectinib administration. No incompliance was observed. If differences in dinner compositions were present throughout the weeks, this would have influenced relative differences to a minimum. If, from a hypothetical point of view, there would be bias, it would have been nondifferential because patients did not know which food would improve or decrease the absorption of alectinib. Nondifferential bias does not influence relative inference and therefore has not influenced our primary outcome; it would only have increased the magnitude of variation. In addition, time-dependent compliance could have influenced the results. Patient adherence could, for instance, be higher at the start of the study. This was, however, partially captured by the randomized nature of this study.
Furthermore, we used a population mean half-life to extrapolate the concentrations to 12 hours after intake. Ideally, individual half-life would have been measured. However, extrapolation was done only for a median of 116 minutes (range, −115 to 180 minutes) and, more importantly, the primary outcome would not have been deviated with an individual half-life because a within-patient comparison was made. Because this study used a within-patient comparison and included 20 patients, it is unlikely that the found difference was due to chance. In addition to that, the bioanalytical accuracy was high, at 96.9% to 99.6%, and the individual exposure for diet B was always lower than for diet A and/or diet C. In addition, regarding the statistics, a Bonferroni correction was applied in this study for multiple testing to minimize the possibility of a type I error.
To overcome the possible deleterious effects of FDIs, therapeutic drug monitoring could be a convenient solution.10,11 With therapeutic drug monitoring, alectinib exposure would be frequently monitored and, based on measured exposure, an intervention would be performed to increase exposure if necessary. To increase exposure, dose increase is frequently applied; however, before dose increase, dietary counseling should be considered in patients treated with alectinib because this intervention is less expensive and simple to implement. Currently, a large clinical trial in the Netherlands is recruiting patients treated with alectinib to determine the prospective effects of therapeutic drug monitoring on survival (ClinicalTrials.gov identifier: NCT05525338).
Conclusions
Patients and physicians should be warned of the detrimental food–alectinib interaction when taken with low-fat yogurt. A self-chosen lunch does not significantly change drug exposure and toxicity. Hence, alectinib intake with lunch could be used as a safe and patient-friendly alternative to breakfast. Patients could benefit from dietary counseling in daily clinical care to optimize alectinib treatment.
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