Junkyu Kim; Min-Ji Kim; Jinyong Kim; Sehhoon Park; Hyun Ae Jung; Se-Hoon Lee; Jin Seok Ahn; Myung-Ju Ahn; Jong-Mu Sun

doi:10.4143/crt.2024.1209

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Original Article Lung and Thoracic cancer Clinical Relevance of Starting Alectinib at a Reduced Dose in Patients with ALK-Positive Non–Small Cell Lung Cancer: Junkyu Kim¹, Min-Ji Kim², Jinyong Kim¹, Sehhoon Park¹, Hyun Ae Jung¹, Se-Hoon Lee¹, Jin Seok Ahn¹, Myung-Ju Ahn¹, Jong-Mu Sun¹; Cancer Research and Treatment : Official Journal of Korean Cancer Association 2026;58(2):434-442.
DOI: https://doi.org/10.4143/crt.2024.1209
Published online: April 24, 2025

¹Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea

²Biomedical Statistics Center, Research Institute for Future Medicine, Samsung Medical Center, Seoul, Korea

Correspondence: Jong-Mu Sun, Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul 60351, Korea
Tel: 82-2-3410-3459 E-mail: jongmu.sun@skku.edu

• Received: December 14, 2024 • Accepted: April 22, 2025

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Abstract

Purpose
Alectinib has been approved for anaplastic lymphoma kinase (ALK)–positive non–small cell lung cancer (NSCLC) at 300 mg twice daily in Japan, lower than global standard of 600 mg twice daily. This study evaluated the clinical relevance of the reduced dose by comparing outcomes between the two doses.
Materials and Methods
This study included patients with advanced ALK-positive NSCLC who received alectinib at Samsung Medical Center, Korea. The progression-free survival (PFS), overall survival, cumulative incidence of central nervous system (CNS) progression, and safety profiles were retrospectively reviewed and compared.
Results
Among 306 patients, 32 and 274 received alectinib at either 300 or 600 mg twice daily, respectively. The 300 mg group showed a slight but not significant advantage in PFS (hazard ratio [HR], 0.82; 95% confidence interval [CI], 0.44 to 1.51; p=0.51) and overall survival (HR, 0.51; 95% CI, 0.20 to 1.21; p=0.13). Superior outcome with 300 mg was remarkable in patients with lower body weight (≤ 60 kg), but diminished in patients with higher body weights. Patients with baseline brain metastasis in the 300 mg group exhibited a slight increase in incidence of CNS failure (HR, 1.76; 95% CI, 0.53 to 5.8; p=0.36). Although the safety profiles were mostly mild, adverse events were more frequent in the 600 mg group, 50% of which requiring dose reduction.
Conclusion
Alectinib at 300 mg twice daily seems an acceptable dose in East Asians with ALK-positive NSCLC. Notably, our data favor 300 mg twice daily in patients with lower body weight and no baseline brain metastasis, considering the more tolerable safety profiles and the potential to reduce medical costs.
Key words: Non-small-cell lung carcinoma, Anaplastic lymphoma kinase, Alectinib

Introduction

Alectinib is an anaplastic lymphoma kinase (ALK)–specific target agent. Following its approval in patients with non–small cell lung cancer (NSCLC) who failed on crizotinib therapy [1], alectinib has been a standard first-line therapy for ALK-positive NSCLC. It has shown superior efficacy in three phase III trials (J-ALEX, ALEX, and ALESIA) compared with crizotinib in treatment-naïve patients with ALK-positive NSCLC [2-4].

However, the optimal dose of alectinib remains unclear. The J-ALEX trial, which included only Japanese patients, validated alectinib 300 mg twice daily, while the ALEX and ALESIA trials, where Asian patients comprised 47% and 100% of the study population, respectively, tested alectinib 600 mg twice daily. Based on these trials, alectinib was approved at different doses between Japan (300 mg twice daily) and the rest of the world (600 mg twice daily). This different approval in doses for a single oncologic drug according to the country appears to be unique for alectinib and needs to be addressed.

When alectinib was first tested in Japan in a dose-defining phase I/II study (AF-001JP) [5], 300 mg twice daily was the highest dose among the planned dose-escalating levels. Combined with no dose-limiting toxicity (DLT) across all levels, the dramatic response rate (93.5%) among 46 crizotinib-naïve patients treated with alectinib 300 mg twice daily resulted in the approval of this dose level in Japan in 2014, and the dose was tested in the subsequent J-ALEX, phase III study. However, another dose-defining phase I/II study (AF-002JG) was performed in the United States, where the phase I dose-escalation cohorts were composed of five dose levels from 300 up to 900 mg twice daily [6]. Seven patients were assigned to each dose level, with no DLT events observed at any level. In the next bridging cohort of the study, which was additionally designed to test a 150 mg capsule newly formulated from the old forms of 20/40 mg capsules, two dose levels (600 and 900 mg twice daily) were compared: two DLT events (grade 3 headache in one patient and grade 3 neutropenia for longer than 7 days in one patient) developed among six patients assigned to 900 mg twice daily, while there were no DLT at 600 mg twice daily. Therefore, the investigators defined 600 mg twice daily as the recommended dose for subsequent trials performed globally. However, whether 600 mg twice daily is a true maximum tolerated dose is uncertain, since grade 3 headache, which had been regarded as a DLT at 900 mg twice daily, was eventually found to be caused by radiation necrosis developed in an irradiated metastatic brain tumor rather than by alectinib therapy [6]. Therefore, by definition, the maximum tolerated dose for alectinib was not within the dose ranges set by the two phase I/II studies [5,6].

Based on prior phase III trials, the clinical efficacy of two alectinib doses is comparable. In the J-ALEX study, the median PFS of alectinib was 34.1 months (vs. 10.1 months for crizotinib; hazard ratio [HR], 0.37; 95% confidence interval [CI], 0.26 to 0.52) by independent review committee (IRC) assessment, whereas, in the ALEX study, it was 34.8 months (vs. 10.9 months for crizotinib; HR, 0.43; 95% CI, 0.32 to 0.58) by investigator assessment [7,8]. Similar results were obtained for the Asian subgroup in the ALEX study (34.8 months vs. 9.6 months; HR, 0.43; 95% CI, 0.32 to 0.58) [8]. Although the recently updated report for the ALESIA study showed longer median PFS for alectinib (41.6 months vs. 11.1 months for crizotinib; HR, 0.33; 95% CI, 0.23 to 0.49) by investigator assessment, it lacked reports by IRC assessment [9]. This needs to be interpreted cautiously since the ALESIA study was an open-label study, and its first report showed more favorable results for alectinib when it was assessed by investigators (HR, 0.22; 95% CI, 0.13 to 0.38) than in the assessment by IRC (HR, 0.37; 95% CI, 0.22 to 0.61) [4].

Based on these contradictory results, while 600 mg twice daily is the approved dose in the Republic of Korea, some physicians opt for a starting dose of 300 mg twice daily, in ALK-positive NSCLC patients to minimize adverse effects and improve treatment adherence, particularly in light of studies indicating efficacy and safety of this regimen in East Asian populations [2,4]. In the current study, we compared the clinical outcomes in patients treated with one of two starting doses of alectinib (300 mg vs. 600 mg). Additionally, we aimed to evaluate the clinical relevance of 300 mg twice daily as a starting dose in countries other than Japan.

Materials and Methods

1. Study participants

This study retrospectively included patients with ALK-positive NSCLC who were treated with alectinib at Samsung Medical Center between June 2017 and October 2023. We excluded patients who were treated with other second-generation ALK tyrosine kinase inhibitors, such as brigatinib and ceritinib, before alectinib.

2. Statistical analysis

The all-data cutoff date for analyses was May 29, 2024. To compare the baseline characteristics between the 300 and 600 mg twice daily groups, the chi-square test or Fisher’s exact test for categorical and independent sample t test for continuous variables were used. The PFS was defined as the time from initiation of alectinib to documentation of either disease progression or death. Overall survival was defined as the time from initiation of alectinib to death from any cause. Patients with no event at the data cutoff date were censored on the last date of follow-up. Survival curves were calculated using the Kaplan-Meier method and compared using the log-rank test and Cox-proportional hazards-regression model. Median follow-up time was estimated by the reverse Kaplan-Meier method. Subgroup analysis of PFS and overall survival was performed based on prior exposure to crizotinib and body weight, as prior usage of crizotinib may impact treatment efficacy. Patients were categorized into three body weight groups, ≤ 60 kg, > 60 to 75 kg, and > 75 kg to show the influence of overweight on efficacy.

Central nervous system (CNS) PFS was evaluated as the time from initiation of alectinib to documentation of objective CNS progression or death resulting from any cause. All patients were evaluated with brain magnetic resonance imaging (MRI) before starting alectinib therapy. Baseline CNS Metastasis was classified as negative if no metastatic lesions were detected on brain MRI performed prior to the initiation of alectinib. To evaluate the effectiveness of alectinib for CNS lesions, we analyzed the cumulative incidence of CNS progression, where CNS progression was considered the primary event, while non-CNS progression and death was considered the competing event. The time to event was defined as the duration from initiation of alectinib to the occurrence of the event of interest. The individuals who experienced competing events were censored at the time of the event. Cause-specific Cox regression models were applied to estimate the effect of alectinib on the risk of CNS progression, non-CNS progression, and death separately. HRs with 95% CIs were reported for each event type.

All p-values were two-sided, and p < 0.05 was statistically significant. Data were analyzed using SAS ver. 9.4 (SAS Institute Inc.).

Results

1. Patient characteristics

A total of 306 patients were treated with alectinib. Thirty-two patients received an initial dose of 300 mg twice daily, while 274 patients received 600 mg twice daily. Table 1 summarizes the baseline characteristics of the patients. There was no significant difference in characteristics between the groups. The mean body weights at starting alectinib therapy were 60.8 kg and 62.2 kg in the 300 mg and 600 mg groups, respectively (p=0.53). More than half of participants in both groups were male and never smokers. Similar proportions in the 300 mg (n=10, 31%) and 600 mg groups (n=99, 36%) received alectinib therapy after crizotinib therapy, and the others received alectinib therapy as their first ALK-targeting agent (p=0.72). However, the 300 mg group included more elderly patients (mean age, 61 vs. 55 years; p=0.019) and fewer patients with baseline brain metastasis (25% vs. 43%, p=0.054) compared with the 600 mg group.

2. PFS and overall survival

The median follow-up duration for PFS was 52.5 and 46.7 months for the 300 and 600 mg groups, respectively. Instances of disease progression or death occurred in 131 patients (11 of 32 patients [32%] in the 300 mg group and 120 of 274 patients [44%] in the 600 mg group). The 300 mg group had a slightly superior PFS outcome compared with the 600 mg group (HR, 0.82; 95% CI, 0.44 to 1.51; p=0.51) (Fig. 1A). The difference in PFS between the two groups did not vary with history of prior crizotinib therapy. Median PFS for 300 mg twice daily was not reached (95% CI, 18.3 to not reached) and 57.6 months (95% CI, 36.9 to not reached) for 600 mg twice daily. In the populations with and without prior crizotinib therapy, the HRs for PFS in the 300 mg group were 0.80 (95% CI, 0.32 to 2.00; p=0.64) and 0.88 (95% CI, 0.38 to 2.05; p=0.77), respectively, compared with the 600 mg group (S1 Fig.).

The median follow-up durations for overall survival were 53.4 and 47.4 months for the 300 and 600 mg groups, respectively. Overall survival was longer in the 300 mg group compared to the 600 mg group (HR, 0.51; 95% CI, 0.21 to 1.25; p=0.13) (Fig. 1B).

3. PFS and overall survival according to baseline body weight

The participants were categorized into three populations according to baseline body weight: ≤ 60 kg, > 60 to 75 kg, and > 75 kg. In the population with lower body weight (≤ 60 kg), the 300 mg group showed slightly superior PFS compared with the 600 mg group (HR, 0.54; 95% CI, 0.20 to 1.49; p=0.23), while no such superiority was observed in the > 60 to 75 kg (HR, 1.35; 95% CI, 0.54 to 3.39; p=0.53) or > 75 kg (HR, 0.96; 95% CI, 0.22 to 4.20; p=0.96) group (Fig. 2). Similarly, in the overall survival analysis, the 300 mg group demonstrated a trend toward a more favorable outcome in the lower body weight group. However, there were no significant differences between the 300 and 600 mg treatment groups across all body weight categories (S2 Fig.).

4. Intracranial PFS and cumulative incidence of CNS progression

Overall CNS PFS in the 300 mg group was not significantly different from that in the 600 mg group (HR, 0.66; 95% CI, 0.20 to 2.14; p=0.65) (Fig. 3A). There was no significant increase in the cumulative incidence of CNS progression in the 300 mg group compared with the 600 mg group (HR, 0.93; 95% CI, 0.28 to 3.06; p=0.90) (Fig. 3B).

However, there were slightly different outcomes when the cumulative incidence of CNS progression was analyzed after patients had been categorized into those with and without baseline brain metastasis. In a population without baseline brain metastasis, there was no CNS progression in either the 300 or 600 mg group. However, in a population with baseline brain metastasis, there was a slightly higher cumulative incidence of CNS progression in the 300 mg group than in the 600 mg group (HR, 1.76; 95% CI, 0.53 to 5.80; p=0.36) (Fig. 3C).

5. Safety profile

Most adverse events were mild or moderate and manageable. However, there was a lower incidence of adverse events in the 300 mg group than in the 600 mg group (Table 2). Adverse events that occurred at a 10 percentage points or greater lower incidence in the 300 mg group compared to the 600 mg were peripheral edema (13% vs. 27%), rash (3% vs. 13%), constipation (9% vs. 30%), myalgia (6% vs. 20%), increase in aspartate aminotransferase (AST)/alanine aminotransferase (ALT) (81% vs. 91%), hyperbilirubinemia (5% vs. 62%), and increased creatinine (34% vs. 50%). Grade 3 or 4 adverse events occurred in only one case (increase in AST/ALT) (3%) in the 300 mg group, while 45 grade 3-4 events (16%) were reported in the 600 mg group.

In the 300 mg group, no dose reduction occurred, while 137 patients (50%) in the 600 mg group underwent dose reduction to 450 mg twice daily (n=52) or 300 mg twice daily (n=85) (Table 2). The primary cause for dose reduction was increase in AST/ALT (41%) or bilirubin (12%), peripheral edema (14%) with additional causes including myalgia (9%), neutropenia or thrombocytopenia (5%), pneumonitis (3%), myositis (1%), constipation (3%), and rash (5%).

In the 300 mg group, two patients (6%) discontinued treatment due to adverse events: one patient achieving complete remission of NSCLC complained about intolerable general weakness, which required discontinuation of alectinib. Another patient discontinued treatment due to elevation in AST/ALT and changed to another second-generation ALK tyrosine kinase inhibitor (TKI). In the 600 mg group, four patients discontinued alectinib with causes of hepatotoxicity, pneumonitis, and pleural effusion. These patients were subsequently transitioned to alternative second-generation ALK TKIs.

Discussion

The maximum tolerated dose can be difficult to define in phase I/II studies using the standard 3+3 dose-escalating design, because of the very tolerable safety profiles of recently developed oncologic agents [10]. Therefore, the optimal dose is chosen using additional methods, such as reevaluation of the overall efficacy and safety based on larger study populations as well as preclinical pharmacokinetics/pharmacodynamics models [11-13]. For example, in a phase I/II study for osimertinib, which is another target agent used for epidermal growth factor receptor (EGFR)–mutant NSCLC, no DLT occurred in the dose-escalation phase from 20 to 240 mg once daily (n=31) [11]. Subsequently, five expansion cohorts demonstrated that while plasma concentration-time curve increased dose-proportionally, the objective response rate plateaued at 80 mg and did not increase at higher dose. Although the toxicity profile suggested that higher doses greater than 80 mg were related to a slightly increased incidence in mild or moderate severity (grade 1 or 2), grade 3-5 adverse rates were 3% or less even at the higher levels. Based on these efficacy and toxicity data, investigators chose 80 mg as a recommended dose for a phase II study [14].

Exposure-response evaluation can be used as another method to support dose optimization. One study showed that a higher average plasma concentration during the first 6 weeks of treatment (C_{average_6 week} > 1,040 nmol/L) was associated with longer PFS for alectinib, based on the retrospective analysis of four study populations (NP28673, J-ALEX, ALEX, and ALESIA) [15]. Interestingly, the plasma concentration was only affected by the body weight of patients among various clinical or laboratory characteristics. In the computed prediction model of the administration of 300 mg twice daily, 69% of the J-ALEX (median body weight, 56.9 kg) population would fall into the high-exposure category, while only 43% and 51% of the ALEX (median body weight, 65.2 kg) and ALESIA (median body weight, 61.0 kg) populations, respectively, would be in the high-exposure category. If 600 mg twice daily were administered, 100%, 92%, and 95% of the populations (J-ALEX, ALEX, and ALESIA, respectively) would fall into the high-exposure category. Although these data justify in part why the approved dose of alectinib is different in Japan from the rest of the world, we must be cautious not to generalize without sufficient evidence. Given that pharmacokinetic data are not affected by ethnic differences [6,15], and body weight is purely individual information, we should not overestimate the data from the computed prediction model and need to individualize the alectinib dose according to the body weight of patients. Different doses according to body weight have been applied for another oncologic drug, amivantamab, with a recommendation of 1,050 mg and 1,400 mg for patients less than 80 kg and those 80 kg or higher, respectively [16]. Our current data showed a different efficacy of 300 mg twice daily compared with that of 600 mg twice daily according to body weight. While the dose of 300 mg twice daily showed slightly superior or comparable survival data compared with 600 mg twice daily in subgroups of patients with lower body weight (≤ 60.0 kg), the lower alectinib dose was slightly inferior to the higher dose in patients with higher body weight (> 60.0-75 kg or > 75 kg). This suggests that the alectinib dose can be individualized according to body weights, and 300 mg twice daily could be a more favorable dose in patients with lower body weights.

Previous studies showed that alectinib was more active for brain metastasis compared with crizotinib with HR ranging from 0.16-0.22 for time to CNS-specific progression [4,17,18]. However, the data varied by baseline brain metastasis. In the subgroup with baseline brain metastasis, the protective effect of alectinib from CNS-specific progression was less dramatic in the J-ALEX study (HR, 0.51; 95% CI, 0.16 to 1.64) than in the ALEX study (HR, 0.18; 95% CI, 0.09 to 0.36). Meanwhile, in the subgroup without baseline brain metastasis, the HR was similar between the two studies (0.19 and 0.14 in J-ALEX and ALEX studies, respectively). In our current study, the 300 mg group showed a slightly inferior outcome for cumulative incidence of CNS progression to the 600 mg group in a population with baseline brain metastasis, while similar CNS efficacy was observed in the population without baseline brain metastasis. Although the brain:plasma ratio of alectinib concentration is relatively high (0.63-0.94) in animal models [19], the optimal dose of alectinib for brain metastatic tumors could be higher than for extracranial tumors. A case report showed that increasing the dose of alectinib to 900 mg twice daily induced CNS responses in patients who had experienced isolated CNS progression with 600 mg twice daily [20]. However, the clinical relevance of increasing the alectinib dose to greater than 600 mg twice daily needs more clinical data and should be tested in an experimental setting, given that increasing the osimertinib dose to 160 mg from a standard dose (80 mg) only resulted in a modest effect on isolated CNS progression [21,22].

Alectinib is a very tolerable agent, and previous studies did not show a significant difference in the rates of serious adverse events by dose in safety profiles (27.2%, 38.8%, and 28.0% in J-ALEX, ALEX, and ALESIA, respectively) or in the proportion of patients with adverse events leading to discontinuation (11.7%, 14.5%, and 11.2% in the same order). As in previous studies, our findings demonstrated that adverse events were mostly mild and manageable in patients on either of the doses. However, the higher dose was related to more frequent adverse events and dose reduction rates. Considering the relatively long-term treatment duration of alectinib, adverse events of any grade could significantly impair patients’ quality of life. Therefore, starting at an alectinib dose of 300 mg is supported.

To generalize our data into clinical practice, our study has an important limitation in that it is a retrospective analysis of a relatively small number of patients, especially only 10% of 300 patients used 300 mg twice daily and many patients had second-line ALK TKI which potentially may be confounding factor. Furthermore, the retrospective nature of this study makes it susceptible to significant selection bias. However, this is the first attempt to evaluate the clinical relevance of alectinib at 300 mg twice daily compared directly with 600 mg twice daily. Based on our study, alectinib 300 mg twice daily seems an acceptable dose. Particularly, 300 mg twice daily may be a feasible treatment option for patients with a body weight of 60 kg or less and no baseline brain metastasis. In addition, with comparable efficacy, 300 mg twice daily was more tolerable than 600 mg twice daily, which may improve patient compliance over the long duration of alectinib therapy. Additionally, the financial burden of treatment would potentially be eased by the lower dosing regimen, which would also improve patient compliance in some countries where many oncologic agents are still expensive compared with their economic status [23].

Electronic Supplementary Material

Supplementary materials are available at Cancer Research and Treatment website (https://www.e-crt.org).

crt-2024-1209_S1_Fig.pdf

crt-2024-1209_S2_Fig.pdf

NOTES

Ethical Statement

This study was approved by the institutional review board at Samsung Medical Center (IRB number 2024-10-039), and the requirement for informed consent was waived because of the retrospective nature of this study.

Author Contributions

Conceived and designed the analysis: Kim J (Junkyu Kim), Park S, Jung HA, Lee SH, Ahn JS, Ahn MJ, Sun JM.

Collected the data: Kim J (Junkyu Kim), Kim J (Jinyong Kim).

Contributed data or analysis tools: Kim J (Junkyu Kim), Kim MJ, Jung HA, Sun JM.

Performed the analysis: Kim J (Junkyu Kim), Kim MJ.

Wrote the paper: Kim J (Junkyu Kim), Kim MJ, Sun JM.

Conflicts of Interest

Conflict of interest relevant to this article was not reported.

Fig. 1.

Progression-free survival (A) and overall survival (B) of the groups treated with alectinib 300 mg and 600 mg twice daily.

Fig. 2.

Progression-free survival according to baseline body weights: (A) ≤ 60 kg, (B) > 60 kg to ≤ 75 kg, (C) > 75 kg.

Fig. 3.

(A) Central nervous system (CNS) progression-free survival. (B) Cumulative incidence of CNS progression. (C) Cumulative incidence of CNS progression in a population with baseline brain metastasis.

Table 1.

Baseline demographics

	300 mg twice daily (n=32)	600 mg twice daily (n=274)	p-value
Age (yr)
Mean±SD	61±15	55±12	0.019
Range	34-95	14-85
Body weight (kg)
Mean±SD	60.8±12.8	62.2±12.0	0.53
Range	37.0-86.3	38.9-124.4
Body weight (kg)
≤ 60	18 (56.2)	128 (46.7)
> 60 to 75	9 (28.1)	106 (38.7)
> 75	5 (15.6)	40 (14.6)
Sex
Male	21 (65.6)	157 (57.3)	0.37
Female	11 (34.3)	117 (42.7)
ECOG performance status
0-1	32 (100)	262 (95.6)	0.23
2	0	12 (4.4)
Smoking history
Never	22 (68.8)	172 (62.8)	0.72^a)
Ex-smoker	6 (18.7)	60 (21.8)
Current smoker	3 (9.4)	37 (13.5)
Unknown	1 (3.1)	5 (1.8)
Histology
Adenocarcinoma	32 (100)	260 (94.8)	> 0.99^a)
Squamous cell carcinoma		8 (2.9)
Others^b)		6 (2.1)
Previous crizotinib therapy	10 (31.2)	99 (36.1)	0.58
Initial stage
Post-operative recurrence	11 (34.3)	61 (22.2)	0.35
Initially advanced	21 (65.6)	213 (77.7)
Baseline metastasis site
Brain	8 (25.0)	117 (42.7)	0.054
Liver	4 (12.5)	41 (15.0)	0.71
Bone	8 (25.0)	89 (32.5)	0.39
Lung	14 (43.8)	91 (33.2)	0.24

Independent t test for continuous variables and chi-square test or Fisher’s exact test for categorical variables. ECOG, Eastern Cooperative Oncology Group; SD, standard deviation.

^a) Fisher’s exact test,

^b) Others category includes poorly differentiated, unclassifiable, adenosquamous, pleomorphic, and signet ring cell carcinomas.

Table 2.

Side effect profile and dose adjustment

	300 mg twice daily (n=32)		600 mg twice daily (n=274)
	Any grade	Grade 3-4	Any grade	Grade 3-4
Peripheral edema	4 (12.5)	0	73 (26.6)	1 (0.3)
Rash	1 (3.1)	0	35 (12.8)	0
Constipation	3 (9.4)	0	82 (30.0)	0
Myalgia	2 (6.2)	0	57 (20.8)	0
Nausea	0	0	14 (5.1)	0
Pneumonitis	0	0	10 (3.6)	1 (0.3)
Anemia	29 (90.6)	0	252 (92.0)	20 (7.2)
Neutropenia	10 (31.2)	0	34 (12.4)	3 (1.1)
Thrombocytopenia	3 (9.4)	0	22 (8.0)	5 (1.8)
Elevated AST/ALT	26 (81.2)	1 (3.1)	249 (90.8)	13 (4.7)
Hyperbilirubinemia	15 (46.9)	0	169 (61.6)	8 (2.9)
Increased creatinine	11 (34.3)	0	136 (49.6)	1 (0.3)
Dose reduction
450 mg twice daily	NA		52 (19.0)
300 mg twice daily	NA		85 (31.0)
Discontinuation	2 (6.2)		4 (1.4)

Values are presented as number (%). AST/ALT, aspartate aminotransferase/alanine aminotransferase; NA, not applicable.

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Clinical Relevance of Starting Alectinib at a Reduced Dose in Patients with ALK-Positive Non–Small Cell Lung Cancer

Cancer Res Treat. 2026;58(2):434-442. Published online April 24, 2025

DOI: https://doi.org/10.4143/crt.2024.1209

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Abstract
Introduction
Materials and Methods
Results
Discussion
Electronic Supplementary Material
NOTES
REFERENCES

Clinical Relevance of Starting Alectinib at a Reduced Dose in Patients with ALK-Positive Non–Small Cell Lung Cancer

Fig. 1. Progression-free survival (A) and overall survival (B) of the groups treated with alectinib 300 mg and 600 mg twice daily.

Fig. 2. Progression-free survival according to baseline body weights: (A) ≤ 60 kg, (B) > 60 kg to ≤ 75 kg, (C) > 75 kg.

Fig. 3. (A) Central nervous system (CNS) progression-free survival. (B) Cumulative incidence of CNS progression. (C) Cumulative incidence of CNS progression in a population with baseline brain metastasis.

Fig. 1.

Fig. 2.

Fig. 3.

Clinical Relevance of Starting Alectinib at a Reduced Dose in Patients with ALK-Positive Non–Small Cell Lung Cancer

	300 mg twice daily (n=32)	600 mg twice daily (n=274)	p-value
Age (yr)
Mean±SD	61±15	55±12	0.019
Range	34-95	14-85
Body weight (kg)
Mean±SD	60.8±12.8	62.2±12.0	0.53
Range	37.0-86.3	38.9-124.4
Body weight (kg)
≤ 60	18 (56.2)	128 (46.7)
> 60 to 75	9 (28.1)	106 (38.7)
> 75	5 (15.6)	40 (14.6)
Sex
Male	21 (65.6)	157 (57.3)	0.37
Female	11 (34.3)	117 (42.7)
ECOG performance status
0-1	32 (100)	262 (95.6)	0.23
2	0	12 (4.4)
Smoking history
Never	22 (68.8)	172 (62.8)	0.72^a)
Ex-smoker	6 (18.7)	60 (21.8)
Current smoker	3 (9.4)	37 (13.5)
Unknown	1 (3.1)	5 (1.8)
Histology
Adenocarcinoma	32 (100)	260 (94.8)	> 0.99^a)
Squamous cell carcinoma		8 (2.9)
Others^b)		6 (2.1)
Previous crizotinib therapy	10 (31.2)	99 (36.1)	0.58
Initial stage
Post-operative recurrence	11 (34.3)	61 (22.2)	0.35
Initially advanced	21 (65.6)	213 (77.7)
Baseline metastasis site
Brain	8 (25.0)	117 (42.7)	0.054
Liver	4 (12.5)	41 (15.0)	0.71
Bone	8 (25.0)	89 (32.5)	0.39
Lung	14 (43.8)	91 (33.2)	0.24

	300 mg twice daily (n=32)		600 mg twice daily (n=274)
	Any grade	Grade 3-4	Any grade	Grade 3-4
Peripheral edema	4 (12.5)	0	73 (26.6)	1 (0.3)
Rash	1 (3.1)	0	35 (12.8)	0
Constipation	3 (9.4)	0	82 (30.0)	0
Myalgia	2 (6.2)	0	57 (20.8)	0
Nausea	0	0	14 (5.1)	0
Pneumonitis	0	0	10 (3.6)	1 (0.3)
Anemia	29 (90.6)	0	252 (92.0)	20 (7.2)
Neutropenia	10 (31.2)	0	34 (12.4)	3 (1.1)
Thrombocytopenia	3 (9.4)	0	22 (8.0)	5 (1.8)
Elevated AST/ALT	26 (81.2)	1 (3.1)	249 (90.8)	13 (4.7)
Hyperbilirubinemia	15 (46.9)	0	169 (61.6)	8 (2.9)
Increased creatinine	11 (34.3)	0	136 (49.6)	1 (0.3)
Dose reduction
450 mg twice daily	NA		52 (19.0)
300 mg twice daily	NA		85 (31.0)
Discontinuation	2 (6.2)		4 (1.4)

Table 1. Baseline demographics

Independent t test for continuous variables and chi-square test or Fisher’s exact test for categorical variables. ECOG, Eastern Cooperative Oncology Group; SD, standard deviation.

Fisher’s exact test,

Others category includes poorly differentiated, unclassifiable, adenosquamous, pleomorphic, and signet ring cell carcinomas.

Table 2. Side effect profile and dose adjustment

Values are presented as number (%). AST/ALT, aspartate aminotransferase/alanine aminotransferase; NA, not applicable.