A Comprehensive Report on Alectinib (Alecensa®): A Targeted Therapy for ALK-Positive Non-Small Cell Lung Cancer

Introduction and Overview

Executive Summary

Alectinib is a highly selective, orally bioavailable, second-generation small molecule inhibitor of Anaplastic Lymphoma Kinase (ALK) tyrosine kinase.[1] Marketed under the brand name Alecensa®, it represents a significant advancement in the targeted therapy of anaplastic lymphoma kinase-positive (ALK-positive) non-small cell lung cancer (NSCLC).[3] Developed by Chugai Pharmaceutical, a member of the Roche Group, alectinib has demonstrated superior efficacy and central nervous system (CNS) activity compared to the first-generation inhibitor, crizotinib.[3] Initially established as a standard of care for metastatic disease, alectinib's approval has recently expanded to include adjuvant treatment for early-stage resected NSCLC. This expansion, based on practice-changing clinical trial data, marks a paradigm shift towards curative-intent therapy in this specific molecularly-defined patient population.[6]

The Clinical Challenge of ALK-Positive NSCLC

ALK gene rearrangements, most commonly resulting in the echinoderm microtubule-associated protein-like 4-ALK (EML4-ALK) fusion oncoprotein, are the primary oncogenic drivers in approximately 4% to 5% of NSCLC cases.[1] This distinct molecular subtype of lung cancer often presents in a unique demographic: younger individuals, typically under the age of 55, who are often never-smokers.[7] A defining clinical feature of ALK-positive NSCLC is its high propensity for metastasizing to the central nervous system (CNS). Brain metastases are a major cause of morbidity and mortality in this population, posing a significant therapeutic challenge.[7]

The advent of targeted therapy with the first-generation ALK inhibitor, crizotinib, revolutionized the management of this disease. However, its efficacy was limited by two major factors: the inevitable development of acquired resistance, often through secondary mutations in the ALK kinase domain, and its poor penetration of the blood-brain barrier, which left the CNS as a sanctuary site for disease progression.[2] This created a critical and urgent unmet medical need for next-generation inhibitors capable of overcoming these limitations.

Alectinib's Role in the Therapeutic Armamentarium

The development of alectinib was a direct and rational response to the clinical failures of its predecessor. It was specifically engineered to be a more potent and selective ALK inhibitor with activity against a broad range of ALK resistance mutations and, crucially, to exhibit excellent CNS penetration.[11] This molecular design translated directly into clinical success. The success of alectinib in pivotal clinical trials has firmly established it as a standard-of-care for both first-line metastatic and, more recently, early-stage adjuvant treatment of ALK-positive NSCLC.[2]

The clinical development trajectory of ALK inhibitors serves as a microcosm of the broader evolution in precision oncology. It illustrates a reactive and iterative "arms race" against tumor evolution. The initial validation of ALK as a druggable target by crizotinib was a landmark achievement. However, the subsequent identification of its clinical weaknesses—acquired resistance and inadequate CNS control—directly spurred the rational design of second-generation agents like alectinib, which were engineered to address these specific failure points.[2] This cycle continues with third-generation inhibitors, such as lorlatinib, which are designed to tackle resistance to second-generation agents.[14] This reveals a fundamental pattern in modern drug development where clinical failure drives scientific innovation, leading to a stepwise improvement in patient outcomes but also creating a constantly shifting and increasingly complex treatment landscape.

Furthermore, the success of the ALINA trial, which evaluated alectinib in the post-surgical setting, has fundamentally reframed the clinical objective for early-stage ALK-positive NSCLC. Prior to this, adjuvant therapy was dominated by platinum-based chemotherapy, which offered only a modest benefit in delaying recurrence, with high rates of relapse still observed.[6] The goal was incremental improvement. The ALINA trial, however, demonstrated an "unprecedented" 76% reduction in the risk of disease recurrence or death.[6] This is not an incremental gain but a transformative one. This magnitude of benefit shifts the clinical conversation from merely delaying recurrence to realistically pursuing a cure. For a patient with a resected ALK-positive tumor, the discussion is no longer just about buying more time but about a tangible opportunity to prevent the cancer from ever returning, the most critical step towards being cured.[7] This has a profound ripple effect, establishing a new, non-negotiable standard of care that mandates routine ALK testing in all early-stage resectable NSCLC to identify every patient who could benefit from this potentially curative-intent therapy.[17]

Identification and Physicochemical Properties

Nomenclature and Identifiers

Alectinib is identified by a variety of names and codes across clinical, regulatory, and research databases, which are essential for accurate cross-referencing.

• Generic Name: Alectinib [1]
• Brand Names: The primary global brand name is Alecensa®. The name Alecensaro is also registered.[1]
• Chemical Name: The systematic IUPAC name is 9-ethyl-6,6-dimethyl-8-[4-(morpholin-4-yl)piperidin-1-yl]-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile.[3] It is classified as an organic heterotetracyclic compound.[2]
• Developmental Code Names/Synonyms: During its development and in early literature, alectinib was referred to by several codes, including CH-5424802 (or CH5424802), RG-7853, RO5424802, and AF-802.[20]
• DrugBank ID: DB11363 [1]
• CAS Number: The Chemical Abstracts Service has assigned two primary numbers: 1256580-46-7 for the alectinib free base and 1256589-74-8 for the hydrochloride salt form used in the final drug product.[3]

Chemical and Molecular Data

The molecular composition and structure of alectinib define its pharmacological properties.

• Molecular Formula: The chemical formula for the free base is C30​H34​N4​O2​. The hydrochloride salt has the formula C30​H35​ClN4​O2​.[23]
• Molecular Weight: The molecular weight of the alectinib free base is 482.62 g/mol. The hydrochloride salt has a molecular weight of 519.09 g/mol.[1]
• Structural Identifiers:
• SMILES: CCC1=CC2=C(C=C1N1CCC(CC1)N1CCOCC1)C(C)(C)C1=C(C3=CC=C(C=C3N1)C#N)C2=O [2]
• InChIKey: KDGFLJKFZUIJMX-UHFFFAOYSA-N [2]
• InChI: InChI=1S/C30H34N4O2/c1-4-20-16-23-24(17-26(20)34-9-7-21(8-10-34)33-11-13-36-14-12-33)30(2,3)29-27(28(23)35)22-6-5-19(18-31)15-25(22)32-29/h5-6,15-17,21,32H,4,7-14H2,1-3H3 [2]
• Chemical Structure: Alectinib possesses a complex tetracyclic framework based on a benzo[b]carbazole core. This rigid scaffold is substituted with several functional groups critical to its activity: an ethyl group at position 9, a cyano group at position 3, and a 4-(morpholin-4-yl)piperidin-1-yl group at position 8. It is structurally classified as a member of morpholines, piperidines, a nitrile, and an aromatic ketone.[2]

Physical Properties

The physical characteristics of alectinib influence its formulation, storage, and handling.

• Appearance: Alectinib hydrochloride is a white to yellow-white crystalline powder, which may also present as a powder with lumps.[23]
• Solubility: It exhibits low solubility in aqueous buffers across the physiological pH range. It is soluble in organic solvents such as dimethyl sulfoxide (DMSO).[22]
• pKa: The pKa of the base has been reported as 7.05, with the strongest basic pKa calculated at 7.59.[23]
• Storage Conditions: For long-term stability, alectinib should be stored at temperatures below -15°C in a well-closed container to protect it from moisture and degradation.[27]

Table 1. Identification and Physicochemical Properties of Alectinib

Property	Value (Alectinib Free Base)	Value (Alectinib Hydrochloride)
Generic Name	Alectinib	Alectinib Hydrochloride
Brand Name	Alecensa®, Alecensaro	Alecensa®, Alecensaro
Chemical Name	9-ethyl-6,6-dimethyl-8-[4-(morpholin-4-yl)piperidin-1-yl]-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile	9-ethyl-6,6-dimethyl-8-[4-(morpholin-4-yl)piperidin-1-yl]-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile hydrochloride
DrugBank ID	DB11363	DBSALT001607
CAS Number	1256580-46-7	1256589-74-8
UNII	LIJ4CT1Z3Y	P9YY73LO6J
Molecular Formula	C30​H34​N4​O2​	C30​H35​ClN4​O2​
Molecular Weight	482.62 g/mol	519.09 g/mol
Appearance	White Solid	White to yellow-white powder
Solubility	Soluble in DMSO	Low aqueous solubility
pKa (Strongest Basic)	7.59 (calculated)	7.05 (base)
SMILES	CCC1=CC2=C(C=C1N1CCC(CC1)N1CCOCC1)C(C)(C)C1=C(C3=CC=C(C=C3N1)C#N)C2=O	N#CC1=CC2=C(C=C1)C3=C(C(C)(C)C4=CC(N5CCC(N6CCOCC6)CC5)=C(CC)C=C4C3=O)N2.[H]Cl
InChIKey	KDGFLJKFZUIJMX-UHFFFAOYSA-N	GYABBVHSRIHYJR-UHFFFAOYSA-N

Data compiled from.[1]

Clinical Pharmacology

Mechanism of Action

Alectinib exerts its antineoplastic effects through the potent and highly selective inhibition of key oncogenic driver kinases.

Primary and Secondary Target Inhibition

The primary molecular target of alectinib is the anaplastic lymphoma kinase (ALK) receptor tyrosine kinase.[1] It acts as an ATP-competitive inhibitor, binding with high affinity to the ATP-binding pocket within the kinase's active domain.[11] This interaction prevents the enzyme from binding ATP and subsequently transferring phosphate groups to its downstream substrates.[27] Alectinib demonstrates potent inhibition of ALK, with a half-maximal inhibitory concentration (

IC50​) of 1.9 nM and a dissociation constant (Kd​) of 2.4 nM in preclinical assays.[11]

In addition to its profound activity against ALK, alectinib also potently inhibits the RET (Rearranged during Transfection) proto-oncogene, another receptor tyrosine kinase implicated in certain cancers.[3] While ALK is the principal target in its approved indications, the dual ALK/RET activity is a notable feature of its pharmacological profile.

Disruption of Downstream Signaling

In ALK-positive cancer cells, the aberrant ALK fusion protein is constitutively active, driving uncontrolled cell growth and survival through several critical signaling pathways. By binding to and inhibiting ALK, alectinib prevents the autophosphorylation of the kinase.[1] This blockade of the initial activation step leads to the disruption of ALK-mediated downstream signaling. Specifically, it prevents the phosphorylation and subsequent activation of key signaling proteins, including Signal Transducer and Activator of Transcription 3 (STAT3) and the protein kinase B (AKT).[1] The inhibition of AKT effectively shuts down the phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway, a central regulator of cell growth, proliferation, and survival.[3]

Cellular Effect

The ultimate consequence of disrupting these oncogenic signaling cascades is the profound inhibition of tumor cell growth. Alectinib's action leads to a reduction in the viability of tumor cells that harbor ALK fusions, amplifications, or activating mutations.[1] Furthermore, by shutting down these pro-survival signals, alectinib effectively induces apoptosis, or programmed cell death, in the cancer cells, leading to tumor shrinkage and disease control.[3]

Pharmacodynamics

The pharmacodynamic properties of alectinib explain its robust clinical activity, particularly its efficacy against resistance mutations and its sustained therapeutic effect.

Activity Against ALK Fusion Proteins and Resistance Mutations

Alectinib is specifically designed to target the EML4-ALK fusion protein, which is the most common ALK rearrangement and the primary oncogenic driver in this NSCLC subtype.[1] A cornerstone of its "second-generation" status is its potent activity against a wide spectrum of ALK mutations that confer resistance to the first-generation inhibitor, crizotinib.[1] This includes clinically relevant mutations such as ALK F1174L (IC50 1 nM) and ALK R1275Q (IC50 3.5 nM).[11] This broad activity provides a mechanistic basis for its clinical utility. The drug was not just empirically tested in patients who had failed prior therapy; it was rationally designed and selected based on its preclinical ability to overcome known mechanisms of resistance, which explains its initial approval pathway and its success in that patient population.

The Role of the Active Metabolite M4

Alectinib is metabolized in the body to its major metabolite, M4. A critical pharmacodynamic feature of alectinib is that M4 is not an inactive byproduct but is itself a potent ALK inhibitor. Preclinical and clinical data consistently show that M4 possesses similar in vitro potency and in vivo activity to the parent drug, alectinib.[1] This dual contribution from both the parent compound and its equally potent metabolite creates a robust and sustained pharmacodynamic effect. Many drugs have metabolites that are less active or inactive, but in this case, M4 circulates at clinically significant concentrations and continues to exert a powerful therapeutic effect as the parent drug is cleared.[13] This provides a "double-hit" on the ALK target, creating a more stable and prolonged period of ALK inhibition than if only the parent drug were active. This sustained pressure on the ALK pathway likely contributes to the depth and durability of responses observed in clinical trials, as the tumor has less opportunity to recover or develop resistance between doses.

Pharmacokinetics (ADME)

The pharmacokinetic profile of alectinib, encompassing its absorption, distribution, metabolism, and excretion (ADME), is well-characterized and provides the mechanistic basis for its dosing schedule and key clinical advantages, including its efficacy in the CNS.

Absorption

• Effect of Food and Bioavailability: Alectinib is administered orally, and its absorption is significantly influenced by food. When taken with a meal, the absolute bioavailability of alectinib is 37%.[3] This finding underscores the clinical instruction to administer the drug with food to ensure optimal and consistent absorption.
• Time to Peak Concentration (Tmax​): Following oral administration with food, peak plasma concentrations of alectinib are reached in approximately 4 to 6 hours.[3]
• Steady State: With the recommended twice-daily dosing regimen, steady-state plasma concentrations of both alectinib and its active metabolite M4 are achieved within 7 days.[3]
• Steady-State Concentrations: At steady state, the peak plasma concentration (Cmax​) of alectinib is approximately 665 ng/mL, and the total exposure over a dosing interval (AUC) is 7430 ng·h/mL. For the active metabolite M4, the corresponding values are a Cmax​ of 246 ng/mL and an AUC of 2810 ng·h/mL.[13]

Distribution

• Plasma Protein Binding: Both alectinib and its active metabolite M4 are extensively bound to human plasma proteins, with binding reported as greater than 99%.[3] This high degree of protein binding is independent of drug concentration.
• Volume of Distribution (Vd​): The geometric mean volume of distribution at steady state (Vss​) for alectinib is 475 L, while for M4 it is a remarkably large 10,093 L.[13] These large values indicate that the drug and its metabolite are not confined to the bloodstream but distribute extensively into peripheral tissues.
• Central Nervous System Penetration: The extensive tissue distribution is the pharmacokinetic basis for one of alectinib's most critical clinical attributes: its ability to effectively penetrate the central nervous system. The drug is consistently described as "CNS-active," a feature that allows it to treat existing brain metastases and, as shown in the ALINA trial, to significantly reduce the risk of CNS recurrence in the adjuvant setting.[11] This property directly addresses a major limitation of the first-generation inhibitor crizotinib.

Metabolism

• Primary Metabolic Pathway: Alectinib is predominantly metabolized in the liver by the cytochrome P450 enzyme system. The primary enzyme responsible for its metabolism is CYP3A4.[2]
• Formation of Active Metabolite: CYP3A4 mediates the conversion of alectinib to its major active metabolite, M4. This metabolite is then also subject to further metabolism by CYP3A4.[2]
• Contribution to Exposure: Together, the parent drug alectinib and the active metabolite M4 account for the vast majority (76%) of the total drug-related material circulating in the plasma, underscoring the significant contribution of M4 to the overall pharmacologic effect.[3]
• Transporter Interactions: In vitro studies indicate that while the metabolite M4 is a substrate for the efflux transporter P-glycoprotein (P-gp), the parent drug alectinib is not.[2]

The dominant role of CYP3A4 in the metabolism of both alectinib and M4 is a "double-edged sword." While it provides a clear metabolic pathway, it also creates a vulnerability, making alectinib highly susceptible to clinically significant drug-drug interactions. Any co-administered medication that strongly inhibits or induces the CYP3A4 enzyme will predictably and significantly alter alectinib exposure. This single metabolic fact has widespread clinical consequences, requiring physicians to be vigilant about medication reconciliation to avoid potential toxicity from inhibitors (e.g., certain antifungals, antibiotics) or loss of efficacy from inducers (e.g., certain anticonvulsants, herbal remedies).

Excretion

• Elimination Half-Life (T1/2​): Alectinib has a long elimination half-life of approximately 33 hours. Its active metabolite M4 has a similarly long half-life of 31 hours.[13] This pharmacokinetic property supports a convenient twice-daily oral dosing regimen, which enhances patient adherence during long-term therapy.
• Clearance (CL): The apparent clearance from plasma is 81.9 L/hr for alectinib and 217 L/hr for M4.[13]
• Primary Route of Elimination: The main route of elimination for alectinib and its metabolites is through the feces. Following a single radiolabeled dose, 84% of the radioactivity was recovered in the feces. Renal excretion is a minor pathway, with less than 0.5% of the dose being excreted in the urine.[13]

Table 2. Key Pharmacokinetic Parameters of Alectinib and its Active Metabolite M4

Parameter	Alectinib	M4 Metabolite
Absolute Bioavailability	37% (with food)	Not Applicable
Time to Peak Plasma Conc. (Tmax​)	4-6 hours	~4 hours
Elimination Half-Life (T1/2​)	33 hours	31 hours
Volume of Distribution (Vss​)	475 L	10,093 L
Plasma Protein Binding	>99%	>99%
Cmax​ (steady-state)	665 ng/mL	246 ng/mL
AUC (steady-state)	7430 ng·h/mL	2810 ng·h/mL
Primary Metabolizing Enzyme	CYP3A4	CYP3A4
Primary Excretion Route	Feces (84% of total dose)	Feces (as metabolite)

Data compiled from.[3]

Clinical Efficacy and Development

The clinical development program for alectinib has been a model of strategic, evidence-based expansion, moving from a second-line therapy for resistant disease to a first-line standard of care in the metastatic setting, and most recently, to a practice-defining role in the early-stage adjuvant setting.

First-Line Treatment of Metastatic ALK+ NSCLC: The ALEX Study

The cornerstone of alectinib's indication in the first-line metastatic setting is the ALEX trial (NCT02075840), a landmark study that established its superiority over the previous standard of care, crizotinib.[5]

Trial Design

ALEX was a global, randomized, multi-center, open-label, active-controlled Phase III trial. It enrolled 303 patients with treatment-naïve, advanced ALK-positive NSCLC. ALK positivity was centrally confirmed using the VENTANA ALK (D5F3) CDx Assay, ensuring a well-defined patient population.[5] Patients were randomized on a 1:1 basis to receive either alectinib at a dose of 600 mg twice daily or crizotinib at 250 mg twice daily.[5]

Progression-Free Survival (PFS)

The primary endpoint of the trial was progression-free survival as assessed by a blinded independent review committee (BIRC). The study met this endpoint decisively. Alectinib demonstrated a statistically significant and clinically profound improvement in PFS compared to crizotinib. The hazard ratio (HR) for disease progression or death was 0.53 (95% Confidence Interval [CI]: 0.38, 0.73; p<0.0001), representing a 47% reduction in the risk of progression or death.[5] Long-term follow-up data has further solidified this benefit, with a reported 5-year overall survival (OS) rate of 62.5% in the alectinib arm, a remarkable outcome for metastatic NSCLC.[33]

Central Nervous System (CNS) Efficacy

A critical secondary objective of the ALEX trial was to evaluate CNS efficacy, a key area of unmet need. Alectinib demonstrated clear superiority in both treating and preventing CNS metastases.

• Response in Existing CNS Lesions: Among the subset of patients who had measurable CNS lesions at baseline, the CNS overall response rate (ORR) was 81% (95% CI: 58, 95) in the alectinib arm, compared to just 50% (95% CI: 28, 72) in the crizotinib arm.[5]
• Prevention of CNS Progression: Alectinib significantly delayed the time to CNS progression. The cumulative incidence of CNS progression at 12 months was substantially lower for patients treated with alectinib compared to crizotinib, highlighting its protective effect on the brain.[33]

Treatment of Metastatic ALK+ NSCLC after Crizotinib Progression

Alectinib's entry into the clinical arena was as a treatment for patients whose disease had progressed on crizotinib. The U.S. Food and Drug Administration (FDA) granted alectinib accelerated approval in December 2015 for patients with ALK-positive metastatic NSCLC who were either intolerant to or had progressed on crizotinib.[2] This initial approval was based on the compelling results from two single-arm, open-label Phase I/II studies (NP28761 and NP28673). In this heavily pre-treated population, alectinib demonstrated impressive and durable anti-tumor activity, with investigator-assessed overall response rates ranging from 38% to 44% and a median duration of response exceeding one year.[3]

Adjuvant Treatment for Early-Stage ALK+ NSCLC: The ALINA Study

The most recent and perhaps most impactful chapter in alectinib's development is its expansion into the early-stage, curative-intent setting, based on the groundbreaking results of the ALINA study (NCT03456076).

Trial Design

ALINA was a global, randomized, open-label, active-controlled Phase III study designed to evaluate the efficacy and safety of adjuvant alectinib compared to the standard of care, platinum-based chemotherapy. The study enrolled 257 patients with completely resected Stage IB (tumors ≥ 4 cm) to Stage IIIA ALK-positive NSCLC, who were at high risk of recurrence.[6] Patients were randomized to receive either alectinib 600 mg twice daily for a duration of two years or four cycles of platinum-based chemotherapy.[35]

Disease-Free Survival (DFS)

The trial met its primary endpoint of disease-free survival with an overwhelming degree of benefit. The results were presented at major international oncology congresses and published in the New England Journal of Medicine, immediately changing clinical practice.[17]

• Magnitude of Benefit: In the overall study population, alectinib reduced the risk of disease recurrence or death by an unprecedented 76% compared to chemotherapy (HR 0.24; 95% CI: 0.13-0.43; p<0.0001).[6]
• Median DFS: The median DFS was not reached in the alectinib arm, as a majority of patients remained disease-free at the time of analysis. In contrast, the median DFS in the chemotherapy arm was 41.3 months.[8]
• Landmark Analysis: The 3-year DFS rate was 88.7% for patients treated with alectinib, compared to just 54.0% for those who received chemotherapy.[38] This benefit was consistent across all subgroups, including by disease stage.

CNS-Specific DFS and Quality of Life

An exploratory analysis of CNS-specific outcomes reinforced the findings from the metastatic setting. Alectinib provided a clinically meaningful benefit, reducing the risk of CNS recurrence or death by 78% (HR 0.22; 95% CI: 0.08-0.58).[9] This demonstrated that adjuvant alectinib can effectively prevent or delay the development of brain metastases. Furthermore, health-related quality of life (HRQoL) data from the trial showed that patients receiving alectinib experienced sustained or improved HRQoL, whereas patients on chemotherapy experienced a significant decline during treatment. This favorable benefit-risk profile is critical when considering a two-year course of therapy in a curative-intent setting.[35]

Biomarker Analysis

An exploratory biomarker analysis from the ALINA trial revealed that the profound DFS benefit of alectinib was consistent regardless of the specific EML4-ALK fusion variant type (e.g., V1 versus V3).[39] This suggests that alectinib is a robust therapy for the broad population of patients with ALK-positive disease, without the need for further molecular stratification by variant type.

Table 3. Summary of Pivotal Alectinib Clinical Trials

Trial Name (Identifier)	Phase	Indication	Patient Population	N	Arms (Drug/Dose)	Primary Endpoint	Key Result (HR, p-value)
ALEX (NCT02075840)	III	1st-Line Metastatic NSCLC	Treatment-Naïve ALK+	303	Alectinib 600 mg BID vs. Crizotinib 250 mg BID	PFS (by BIRC)	HR 0.53 (95% CI: 0.38-0.73), p<0.0001
ALINA (NCT03456076)	III	Adjuvant Early-Stage NSCLC	Resected Stage IB-IIIA ALK+	257	Alectinib 600 mg BID (2 yrs) vs. Platinum-based Chemo	DFS	HR 0.24 (95% CI: 0.13-0.43), p<0.0001
NP28673 / NP28761	I/II	2nd-Line+ Metastatic NSCLC	Post-Crizotinib ALK+	225	Alectinib 600 mg BID	ORR (by IRC)	ORR 38-44%

Data compiled from.[3]

Safety and Tolerability Profile

The safety profile of alectinib has been extensively characterized through a robust clinical trial program, including pooled data from over 500 patients across studies in both the metastatic and adjuvant settings.[40] While generally considered to have a manageable safety profile, particularly in comparison to chemotherapy and other ALK inhibitors, alectinib is associated with several clinically significant adverse reactions that require proactive monitoring and management.

Overview of Adverse Reactions (ARs)

The most frequently reported adverse reactions (occurring in ≥20% of patients) are typically low-grade and include hepatotoxicity (manifesting as elevated liver enzymes), constipation, fatigue, myalgia (muscle pain), edema (swelling), and rash.[1] The overall safety profile in the adjuvant setting (ALINA trial) was consistent with that observed in the metastatic setting, with no new or unexpected safety signals identified.[6]

A subtle but important difference can be observed in the safety data between the metastatic (ALEX) and adjuvant (ALINA) settings. This likely reflects the healthier baseline population in the early-stage trial. Patients in an adjuvant trial have undergone curative-intent surgery and generally have a better performance status and lower overall tumor burden than patients presenting with first-line metastatic disease. Comparing the safety data from the prescribing information, while the types of adverse events are consistent, the incidence of serious adverse reactions (13% in ALINA vs. 28% in ALEX) and fatal adverse reactions (0% in ALINA vs. 3.3% in ALEX) appears to be lower in the adjuvant setting.[41] This suggests that tolerability may be better in the early-stage population, which is a crucial piece of information for clinicians counseling patients about embarking on a two-year course of adjuvant therapy.

Warnings and Precautions (Detailed Analysis)

The prescribing information for alectinib includes several important warnings and precautions, highlighting the need for careful patient monitoring.

• Hepatotoxicity: This is the most common and one of the most clinically significant risks associated with alectinib. In pooled safety data, some degree of hepatotoxicity (elevated liver transaminases) occurred in 41% of patients, with rates as high as 61% in the ALINA study. Grade 3 or higher events occurred in approximately 5-8% of patients. The onset is typically early, with most elevations occurring within the first 3 months of treatment. This risk necessitates a structured monitoring program: liver function tests (ALT, AST, and total bilirubin) must be monitored every 2 weeks for the first 3 months of therapy, and then monthly thereafter and as clinically indicated. Depending on the severity of the elevation, alectinib may need to be withheld and resumed at a reduced dose, or in severe cases, permanently discontinued.[2]
• Interstitial Lung Disease (ILD)/Pneumonitis: Though rare, occurring in approximately 1.3% of patients, ILD/Pneumonitis is a serious and potentially fatal adverse reaction. Patients should be counseled to report any new or worsening respiratory symptoms, such as dyspnea, cough, or fever. If ILD/Pneumonitis is suspected, alectinib must be immediately withheld and permanently discontinued if no other cause is identified.[1]
• Renal Impairment: Increases in serum creatinine, indicating renal impairment, were observed in 12-16% of patients, with Grade 3 or higher events in approximately 1.7%. Fatal events have been reported. Renal function should be monitored, and dose modifications are required for Grade 3 toxicity, with permanent discontinuation for Grade 4 toxicity.[13]
• Bradycardia: Alectinib can cause a slowing of the heart rate. Symptomatic bradycardia occurred in 11% of patients in pooled analyses. Regular monitoring of heart rate and blood pressure is required. Caution is advised when co-administering alectinib with other medications known to cause bradycardia (e.g., beta-blockers, calcium channel blockers). For symptomatic or life-threatening bradycardia, dose interruption, reduction, or permanent discontinuation may be necessary.[1]
• Severe Myalgia and Creatine Phosphokinase (CPK) Elevation: Myalgia is a common side effect (31-34%), but it can be severe and accompanied by significant elevations in creatine phosphokinase (CPK), an indicator of muscle damage. Elevated CPK occurred in 56-77% of patients across studies, with Grade 3 or higher elevations in 6-8%. Patients should be advised to report any unexplained muscle pain, tenderness, or weakness. CPK levels should be assessed every 2 weeks for the first month of treatment and as clinically indicated thereafter. Dose modification or interruption may be required based on the severity.[1]
• Hemolytic Anemia: This was identified as a risk in the postmarketing setting and was prospectively collected in the ALINA study, where it was observed in 3.1% of patients. This condition involves the premature destruction of red blood cells and can occur even with a negative direct antiglobulin test (DAT). If hemolytic anemia is suspected, alectinib should be withheld and appropriate laboratory testing initiated.[13]
• Embryo-Fetal Toxicity: Based on its mechanism of action and findings in animal studies, alectinib can cause harm to a developing fetus. It is teratogenic. Therefore, effective contraception is mandatory for females of reproductive potential during treatment and for 5 weeks after the final dose. Males with female partners of reproductive potential must also use effective contraception during treatment and for 3 months following the final dose.[1]

The extensive list of warnings and the requirement for proactive monitoring underscore a critical point: the successful and safe use of alectinib is intrinsically linked to physician vigilance and a robust supportive care infrastructure. A "prescribe and forget" approach is not appropriate. The full benefit of this targeted therapy can only be realized when it is coupled with structured monitoring programs and thorough patient education on recognizing and reporting key symptoms.

Adverse Reaction Incidence

The following table summarizes the incidence of the most common adverse reactions observed in the pivotal ALEX (metastatic) and ALINA (adjuvant) trials, providing a comparative view of the safety profile in different clinical settings.

Table 4. Incidence of Adverse Reactions (≥10%) in the Alectinib Arms of the ALEX and ALINA Trials

Adverse Reaction	ALEX (Metastatic, N=152)	ALINA (Adjuvant, N=129)
	All Grades (%)	Grade 3-4 (%)
Laboratory Abnormalities
Anemia	62	7
Increased AST	50	6
Increased Alkaline Phosphatase	50	0
Increased CPK	37	2.8
Hyperbilirubinemia	54	5
Increased ALT	40	6
Increased Creatinine	38	4.1
Hyperglycemia	22	2.2
Hypocalcemia	29	0
Hypokalemia	17	2
Lymphopenia	14	1.4
Hypophosphatemia	9	1.4
Hyponatremia	18	6
Clinical Adverse Reactions
Constipation	34	0
Fatigue	26	1.3
Myalgia	23	0
Edema	22	0.7
Cough	19	0
Rash	15	0.7
Nausea	14	0.7
Dysgeusia	3.3	0
Increased Weight	9.9	0
Diarrhea	12	0
Bradycardia	11	0
Headache	17	0

Data compiled from [13] and.[41]

Dosing, Administration, and Drug Interactions

Recommended Dosing and Administration

Adherence to the correct dosing and administration schedule is critical for achieving optimal therapeutic outcomes with alectinib.

• Standard Dose: The recommended dose of alectinib is 600 mg taken orally twice daily (BID).[5]
• Administration with Food: Alectinib capsules should be taken with food. This is crucial as food significantly increases the drug's bioavailability, ensuring adequate and consistent absorption.[3]
• Duration of Therapy: The duration of treatment depends on the clinical setting:
• Metastatic NSCLC: Treatment should be continued until the patient experiences disease progression or unacceptable toxicity.[13]
• Adjuvant NSCLC: In the post-surgical setting, alectinib is administered for a fixed duration of two years, unless there is disease recurrence or unacceptable toxicity that necessitates earlier discontinuation.[8]
• Dose Modifications for Adverse Reactions: A structured dose reduction schedule is outlined in the prescribing information to manage toxicity. The first dose reduction is to 450 mg BID, and the second is to 300 mg BID. If a patient is unable to tolerate the 300 mg BID dose, alectinib should be permanently discontinued.[13] Specific guidance for withholding, reducing, or discontinuing the drug is provided for key toxicities such as hepatotoxicity, ILD/pneumonitis, renal impairment, and bradycardia.[40]
• Management of Missed or Vomited Doses: If a patient misses a dose or vomits after taking a dose, they should not take an extra dose to make up for it. They should simply take the next dose at its regularly scheduled time.[13]

Drug-Drug Interactions (DDIs)

Alectinib's metabolism via CYP3A4 makes it highly susceptible to drug-drug interactions. Careful medication reconciliation is essential for all patients starting alectinib.

CYP3A4-Mediated Interactions

As a substrate of CYP3A4, alectinib's plasma concentrations can be significantly altered by co-administration of strong inhibitors or inducers of this enzyme.[3]

• Strong CYP3A4 Inhibitors: Drugs that strongly inhibit CYP3A4 (e.g., ketoconazole, itraconazole, clarithromycin, ritonavir, grapefruit juice) can substantially increase the plasma concentrations of alectinib and its active metabolite M4. This increased exposure elevates the risk of adverse reactions. Concurrent use of strong CYP3A4 inhibitors should be avoided. If co-administration is unavoidable, patients should be monitored more frequently for alectinib-related toxicities.[1]
• Strong CYP3A4 Inducers: Drugs that strongly induce CYP3A4 (e.g., rifampin, carbamazepine, phenytoin, St. John's Wort) can significantly decrease the plasma concentrations of alectinib and M4. This can lead to a loss of therapeutic efficacy. Concurrent use of strong CYP3A4 inducers with alectinib should be avoided.[1]

Other Clinically Relevant Interactions

Beyond CYP3A4 interactions, alectinib may interact with other medications through various mechanisms.

• Drugs that Increase Risk of Methemoglobinemia: Co-administration with certain local anesthetics (e.g., benzocaine, lidocaine, prilocaine) can increase the risk of methemoglobinemia, a rare but serious blood disorder.[1]
• Drugs with Additive Toxicities: Caution should be exercised when using alectinib with other drugs that can cause similar adverse effects, such as other agents that can cause bradycardia or hepatotoxicity.
• Substrates of BCRP or P-gp: Alectinib and M4 may inhibit certain drug transporters, potentially increasing the concentration of co-administered drugs that are substrates of these transporters. For example, alectinib may decrease the excretion of brigatinib, leading to higher serum levels of that drug.[1]

The following table highlights some of the most clinically significant drug-drug interactions.

Table 5. Clinically Significant Drug-Drug Interactions with Alectinib

Interacting Drug/Class	Effect on Alectinib/M4	Mechanism	Clinical Recommendation
Strong CYP3A4 Inhibitors (e.g., Ketoconazole, Itraconazole, Clarithromycin, Atazanavir, Grapefruit)	Increased plasma concentration of alectinib and M4	Inhibition of CYP3A4-mediated metabolism	Avoid co-administration. If unavoidable, monitor closely for alectinib toxicity.
Strong CYP3A4 Inducers (e.g., Rifampin, Carbamazepine, Phenytoin, St. John's Wort, Enzalutamide)	Decreased plasma concentration of alectinib and M4	Induction of CYP3A4-mediated metabolism	Avoid co-administration due to risk of reduced efficacy.
P-gp Substrates (e.g., Brigatinib)	Alectinib may increase the concentration of the interacting drug	Inhibition of P-gp-mediated efflux by alectinib	Monitor for toxicity of the co-administered drug.
Drugs Causing Bradycardia (e.g., beta-blockers, diltiazem, verapamil, digoxin)	Additive pharmacodynamic effect	Additive heart rate-lowering effects	Monitor heart rate and blood pressure frequently. Dose modification of one or both agents may be necessary.
Local Anesthetics (e.g., Benzocaine, Prilocaine)	Increased risk of methemoglobinemia	Additive pharmacodynamic effect	Use with caution and monitor for signs of methemoglobinemia.

Data compiled from.[1]

Regulatory and Commercial Landscape

Global Regulatory Approvals and Timeline

Alectinib's path to becoming a global standard of care has been marked by a series of timely regulatory approvals across major jurisdictions, often facilitated by expedited review programs that recognized its significant clinical benefit.

• Japan (PMDA): Alectinib was first approved for medical use in Japan in July 2014 for the treatment of ALK fusion-gene positive, unresectable, advanced, or recurrent NSCLC.[3] Japan also holds an approval for the additional indication of recurrent or refractory ALK fusion gene-positive anaplastic large-cell lymphoma (ALCL).[12]
• United States (FDA): The U.S. FDA has granted a series of approvals that reflect alectinib's expanding evidence base:
• December 2015: An accelerated approval was granted for the treatment of patients with ALK-positive metastatic NSCLC whose disease had progressed on, or who were intolerant to, crizotinib.[2]
• November 2017: Following the results of the ALEX trial, the FDA granted regular approval for the first-line treatment of patients with ALK-positive metastatic NSCLC.[5]
• April 2024: In a landmark decision, the FDA approved alectinib for adjuvant treatment following tumor resection in patients with ALK-positive NSCLC (tumors ≥ 4 cm or node positive). This application was granted Priority Review and Orphan Drug Designation and was reviewed under the FDA's Real-Time Oncology Review (RTOR) pilot program, leading to an approval one month ahead of the goal date.[3]
• European Union (EMA): The European Commission has followed a similar trajectory:
• February 2017: Alectinib was first authorized for use in the EU.[2] The initial indications covered first-line treatment of advanced ALK-positive NSCLC and treatment of patients previously treated with crizotinib.[2]
• April 2024: The Committee for Medicinal Products for Human Use (CHMP) issued a positive opinion recommending the approval of the adjuvant indication.[3]
• June 2024: The European Commission granted full approval for alectinib as an adjuvant monotherapy for adult patients with resected, high-risk ALK-positive NSCLC.[3]
• Other Regions: Alectinib is widely available globally, with approvals in over 100 countries for metastatic disease and in over 90 countries for the post-crizotinib setting.[12] The recent adjuvant approval in the U.S. and Europe was part of a concurrent submission and review process among international partners under Project Orbis, an initiative of the FDA's Oncology Center of Excellence, involving collaboration with agencies in Australia, Canada, Israel, Switzerland, and the United Kingdom.[8]

Commercial Information

• Developer and Manufacturer: Alectinib was created at the Kamakura Research Laboratories of Chugai Pharmaceutical Co., Ltd., a member of the Roche Group. It is marketed globally by Roche and its U.S. affiliate, Genentech.[3]
• Intellectual Property and Generic Availability: Alectinib is protected by a robust patent portfolio. Key patents covering the tetracyclic compound itself, its composition, and its high-dose formulation are issued and have expiration dates extending into the 2030s (e.g., 2031, 2032, 2035).[21] This ensures a long period of market exclusivity. As a result, there is currently no therapeutically equivalent generic version of Alecensa available in the United States or other major markets.[21]

Comparative Analysis and Future Directions

Comparative Efficacy and Safety vs. Other ALK Inhibitors

The treatment landscape for ALK-positive NSCLC is dynamic, with several generations of inhibitors available. Alectinib's position is best understood through comparison with its competitors.

• Alectinib vs. Crizotinib (1st Generation): The evidence from the head-to-head ALEX trial is unequivocal. Alectinib is superior to crizotinib across all key efficacy endpoints, including progression-free survival, overall survival, and CNS efficacy. It also has a more favorable and manageable safety profile.[5] Alectinib has therefore replaced crizotinib as the standard of care for first-line treatment.
• Alectinib vs. Other 2nd Generation Inhibitors (Brigatinib, Ceritinib): Alectinib has demonstrated a better safety profile than ceritinib.[14] Direct head-to-head comparisons with brigatinib are lacking, but both are considered highly effective second-generation options. Network meta-analyses place them similarly in terms of efficacy, with nuanced differences in their safety profiles.
• Alectinib vs. Lorlatinib (3rd Generation): This represents the most critical and nuanced comparison in current clinical practice. As no direct head-to-head trial has been completed, the comparison relies on indirect evidence from network meta-analyses and cross-trial comparisons of their respective pivotal studies (ALEX for alectinib, CROWN for lorlatinib).
• Efficacy: The data suggests a potential efficacy advantage for lorlatinib. Network meta-analyses indicate that lorlatinib may have a superior PFS and a higher intracranial response rate.[14] The 5-year follow-up from the CROWN study, showing a median PFS that has not yet been reached and a 5-year PFS rate of 60%, is an unprecedented result in metastatic NSCLC and sets a new benchmark.[51]
• Safety: The safety profiles differ significantly. Lorlatinib is associated with a higher incidence of Grade 3 or higher adverse events, with a unique toxicity profile that includes hyperlipidemia (requiring management with statins) and CNS effects such as cognitive and mood changes. Alectinib, while having its own set of required monitoring, is generally considered to have a more favorable long-term toxicity profile, particularly regarding these specific AEs.[33]
• Overall Survival: This is a key differentiator. To date, alectinib is the only next-generation ALK inhibitor that has demonstrated a statistically significant overall survival benefit compared to crizotinib in a randomized Phase III trial.[15] The OS data for lorlatinib from the CROWN trial are still immature.

This evidence creates a fundamental trade-off in clinical decision-making. The choice between first-line alectinib and lorlatinib is not straightforward and represents a complex balance between maximizing initial disease control (PFS), for which lorlatinib appears superior, versus selecting a therapy with a proven overall survival benefit and a potentially more favorable long-term toxicity profile (alectinib). This decision must be individualized. For instance, a physician might prioritize the maximal CNS control offered by lorlatinib for a young patient with extensive brain metastases at baseline. Conversely, for an older patient or one with concerns about cognitive or metabolic side effects, alectinib might be the preferred choice due to its better tolerability and established OS track record. This highlights that there is no single "right" answer; the choice is nuanced and must be based on a careful consideration of patient characteristics, disease burden, and a process of shared decision-making.

Ongoing Research and Future Applications

Research continues to refine the role of alectinib and explore new applications.

• Active Clinical Trials: Alectinib is being actively investigated in several important clinical trials, including studies in pediatric populations with ALK-fusion positive solid or CNS tumors, in combination with stereotactic radiosurgery for patients with brain metastases, in tumor-agnostic "basket" trials like TAPISTRY for any ALK-positive solid tumor, and in patients with locally advanced, unresectable Stage III NSCLC.[52]
• Treatment Beyond Progression: A new paradigm is emerging that challenges the traditional model of abandoning a targeted therapy at the first sign of resistance. Retrospective data suggests that in cases of "oligoprogression" (progression in a limited number of sites), continuing alectinib while applying local ablative therapy (like radiation) to the progressing sites can provide significant continued benefit, with one study reporting a median PFS of 8 months with this strategy.[53] This approach suggests that the bulk of the tumor may remain sensitive to the drug, and a more sophisticated strategy of continuing systemic pressure while "mopping up" resistant clones can maximize the benefit from a single agent and delay the need to switch therapies.
• Real-World Evidence: Studies are ongoing to confirm the efficacy and safety of adjuvant alectinib outside the controlled environment of a clinical trial.[54] Other studies are using real-world data to compare the effectiveness of an upfront alectinib strategy versus a sequential approach of crizotinib followed by alectinib.[55]

Unmet Needs and Future Perspectives

Despite the success of alectinib, significant challenges remain.

• Acquired Resistance: In the metastatic setting, acquired resistance to alectinib eventually develops in most patients.[53] A deep understanding of the molecular mechanisms of this resistance—whether through on-target secondary ALK mutations or the activation of bypass signaling pathways—is critical for developing effective subsequent lines of therapy and for rationally sequencing available agents.
• Optimal Sequencing: The ideal sequence of ALK inhibitors remains an area of intense clinical debate. The question of whether to use a second-generation inhibitor like alectinib first, followed by a third-generation inhibitor like lorlatinib at progression, or to use the most potent agent, lorlatinib, upfront, has profound implications for cumulative toxicity, cost-effectiveness, and ultimately, overall survival. Head-to-head trials are needed to resolve this question.
• Duration of Adjuvant Therapy: While the ALINA trial established a two-year duration for adjuvant alectinib, the optimal duration is an open question. Longer-term follow-up from ALINA and future studies will be needed to determine if a longer course could provide further benefit or if a shorter course could be sufficient for some patients, potentially personalizing therapy based on risk of recurrence.[44]

Conclusion and Expert Recommendations

Synthesis of Alectinib's Profile

Alectinib has unequivocally established itself as a cornerstone in the management of ALK-positive non-small cell lung cancer. It is a highly potent and selective second-generation ALK inhibitor with a well-defined mechanism of action. Its predictable pharmacokinetic profile, which enables excellent central nervous system activity, directly addresses a key clinical vulnerability of this disease. Its safety profile, while requiring diligent monitoring for specific toxicities, is generally manageable and favorable compared to many other systemic cancer therapies.

Transformative Clinical Impact

The clinical impact of alectinib has been transformative. The evidence from the ALEX trial redefined the standard of care for first-line metastatic ALK-positive NSCLC by demonstrating clear superiority over crizotinib in progression-free survival, overall survival, and CNS control. More recently, its approval in the adjuvant setting, based on the unprecedented disease-free survival benefit observed in the ALINA trial, represents a landmark achievement. This has shifted the treatment paradigm for early-stage disease, offering a potentially curative-intent therapy where previously only modest improvements were possible.

Expert Recommendations

Based on the comprehensive evidence available, the following recommendations are made for the optimal use of alectinib in clinical practice:

• Biomarker Testing: High-quality, validated ALK testing is mandatory for all patients diagnosed with non-small cell lung cancer, regardless of stage. This includes routine testing of resected tumor tissue from patients with early-stage (Stage IB-IIIA) disease to ensure that all eligible candidates for this practice-changing adjuvant therapy are identified.
• Place in Therapy:
• Adjuvant Setting: For patients with completely resected, high-risk (Stage IB with tumors ≥ 4 cm, or Stage II-IIIA) ALK-positive NSCLC, alectinib (600 mg BID for two years) should be considered the standard of care, having demonstrated a dramatic reduction in the risk of disease recurrence compared to platinum-based chemotherapy.
• Metastatic Setting: Alectinib remains a premier and highly appropriate choice for the first-line treatment of ALK-positive metastatic NSCLC. It offers a robust and well-established balance of profound efficacy (including a proven overall survival benefit over crizotinib) and a favorable long-term safety profile. The decision between first-line alectinib and lorlatinib should be individualized based on a thorough discussion of the trade-offs between progression-free survival, overall survival data maturity, and toxicity profiles.
• Patient Management and Monitoring: The safe and effective use of alectinib is contingent on careful patient management.
• Clinicians must adhere strictly to the recommended monitoring schedules, particularly for hepatotoxicity (LFTs every 2 weeks for 3 months, then monthly) and CPK elevation (every 2 weeks for 1 month). Regular monitoring of heart rate, blood pressure, and renal function is also essential.
• A thorough medication review at baseline and throughout treatment is critical to identify and manage the significant risk of CYP3A4-mediated drug-drug interactions.
• Patient education is paramount. Patients must be counseled on the key symptoms to report (e.g., new respiratory symptoms, muscle pain, signs of liver dysfunction) and be made fully aware of the critical importance of using effective contraception due to the drug's teratogenic potential.

Works cited

1. Alectinib: Uses, Interactions, Mechanism of Action | DrugBank Online, accessed July 30, 2025, https://go.drugbank.com/drugs/DB11363
2. Alectinib | C30H34N4O2 | CID 49806720 - PubChem, accessed July 30, 2025, https://pubchem.ncbi.nlm.nih.gov/compound/Alectinib
3. Alectinib - Wikipedia, accessed July 30, 2025, https://en.wikipedia.org/wiki/Alectinib
4. en.wikipedia.org, accessed July 30, 2025, https://en.wikipedia.org/wiki/Alectinib#:~:text=Alectinib%20(INN)%2C%20sold%20under,anaplastic%20lymphoma%20kinase%20(ALK).
5. Alectinib approved for (ALK) positive metastatic non-small cell lung cancer (NSCLC) | FDA, accessed July 30, 2025, https://www.fda.gov/drugs/resources-information-approved-drugs/alectinib-approved-alk-positive-metastatic-non-small-cell-lung-cancer-nsclc
6. FDA Approves Genentech's Alecensa as First Adjuvant Treatment for People With ALK-Positive Early-Stage Lung Cancer, accessed July 30, 2025, https://www.gene.com/media/press-releases/15023/2024-04-18/fda-approves-genentechs-alecensa-as-firs
7. FDA Approves Alectinib for ALK-Positive Lung Cancer - NCI, accessed July 30, 2025, https://www.cancer.gov/news-events/cancer-currents-blog/2024/fda-alectinib-lung-cancer-alk-positive
8. FDA Approves Alectinib as Adjuvant Treatment for ALK-positive Non-Small Cell Lung Cancer | ESMO, accessed July 30, 2025, https://www.esmo.org/oncology-news/fda-approves-alectinib-as-adjuvant-treatment-for-alk-positive-non-small-cell-lung-cancer
9. Adjuvant Alectinib Significantly Improves Disease-Free Survival in Patients with Resected ALK-positive Stage IB, II, or IIIA NSCLC | ESMO, accessed July 30, 2025, https://www.esmo.org/oncology-news/adjuvant-alectinib-significantly-improves-disease-free-survival-in-patients-with-resected-alk-positive-stage-ib-ii-or-iiia-nsclc
10. Cost-effectiveness of first-line versus second-line use of brigatinib followed by lorlatinib in patients with ALK-positive non-small cell lung cancer - Frontiers, accessed July 30, 2025, https://www.frontiersin.org/journals/public-health/articles/10.3389/fpubh.2024.1213318/full
11. Alectinib (CH5424802) | ALK Inhibitor - MedchemExpress.com, accessed July 30, 2025, https://www.medchemexpress.com/CH5424802.html
12. Alecensa (alectinib) - Roche, accessed July 30, 2025, https://www.roche.com/solutions/pharma/productid-d05457a9-edd8-480b-a482-510c56badc74
13. Alecensa (alectinib) dosing, indications, interactions, adverse effects ..., accessed July 30, 2025, https://reference.medscape.com/drug/alecensa-alectinib-1000067
14. Comparison of lorlatinib, alectinib and brigatinib in ALK inhibitor–naive/untreated ALK-positive advanced non-small-cell lung cancer: a systematic review and network meta-analysis - ResearchGate, accessed July 30, 2025, https://www.researchgate.net/publication/352515945_Comparison_of_lorlatinib_alectinib_and_brigatinib_in_ALK_inhibitor-naiveuntreated_ALK-positive_advanced_non-small-cell_lung_cancer_a_systematic_review_and_network_meta-analysis
15. Comparing efficacy and safety of upfront treatment strategies for anaplastic lymphoma kinase-positive non-small cell lung cancer: a network meta-analysis - PubMed Central, accessed July 30, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC10784113/
16. European Commission approves Roche's Alecensa as the first and only targeted adjuvant treatment for people with ALK-positive early-stage lung cancer, accessed July 30, 2025, https://www.roche.com/media/releases/med-cor-2024-06-10
17. Alecensa Approved by FDA as the First Adjuvant Treatment for People with ALK-Positive Early-Stage Non-Small Cell Lung Cancer | News | CHUGAI PHARMACEUTICAL CO., LTD., accessed July 30, 2025, https://www.chugai-pharm.co.jp/english/news/detail/20240419173000_1067.html
18. Alecensa Approved by the European Commission as the First Adjuvant Treatment for People with ALK-Positive Early-Stage Non-Small Cell Lung Cancer | News | CHUGAI PHARMACEUTICAL CO., LTD., accessed July 30, 2025, https://www.chugai-pharm.co.jp/english/news/detail/20240610170000_1076.html
19. Alectinib - brand name list from Drugs.com, accessed July 30, 2025, https://www.drugs.com/ingredient/alectinib.html
20. Definition of alectinib - NCI Drug Dictionary, accessed July 30, 2025, https://www.cancer.gov/publications/dictionaries/cancer-drug/def/alectinib
21. Generic Alecensa Availability - Drugs.com, accessed July 30, 2025, https://www.drugs.com/availability/generic-alecensa.html
22. CH5424802 (Alectinib, RO5424802, CAS Number: 1256580-46-7) | Cayman Chemical, accessed July 30, 2025, https://www.caymanchem.com/product/18516/ch5424802
23. AusPAR Attachment 1: Product Information for Alectinib hydrochloride - Therapeutic Goods Administration (TGA), accessed July 30, 2025, https://www.tga.gov.au/sites/default/files/auspar-alectinib-hydrochloride-171127-pi.pdf
24. Chemical structure of alectinib | Download Scientific Diagram - ResearchGate, accessed July 30, 2025, https://www.researchgate.net/figure/Chemical-structure-of-alectinib_fig1_336234686
25. CAS 1256580-46-7 Alectinib - BOC Sciences, accessed July 30, 2025, https://www.bocsci.com/product/alectinib-cas-1256580-46-7-454466.html
26. Alectinib HCl | AF 802 | CH5424802 | RO5424802 | CAS#1256580-46-7 | 1256589-74-8 | ALK inhibitor | MedKoo Biosciences, accessed July 30, 2025, https://www.medkoo.com/products/8915
27. Alectinib | 1256580-46-7 | FA75280 - Biosynth, accessed July 30, 2025, https://www.biosynth.com/p/FA75280/1256580-46-7-alectinib
28. Alectinib | Cell Signaling Technology, accessed July 30, 2025, https://www.cellsignal.com/products/activators-inhibitors/alectinib/31443
29. Alectinib hydrochloride - Chemical Details, accessed July 30, 2025, https://comptox.epa.gov/dashboard/chemical/details/DTXCID2077332
30. Alectinib hydrochloride | DrugBank Online, accessed July 30, 2025, https://go.drugbank.com/salts/DBSALT001607
31. 3D structure for Alectinib (DB11363) | DrugBank Online, accessed July 30, 2025, https://go.drugbank.com/structures/small_molecule_drugs/DB11363
32. NSCLC, Squamous or Non-Squamous Completed Phase 3 Trials for Alectinib (DB11363), accessed July 30, 2025, https://go.drugbank.com/indications/DBCOND0130187/clinical_trials/DB11363?phase=3&status=completed
33. Alectinib vs. Lorlatinib in the Front-Line Setting for ALK-Rearranged Non-Small-Cell Lung Cancer (NSCLC): A Deep Dive into the Main Differences across ALEX and CROWN Phase 3 Trials - MDPI, accessed July 30, 2025, https://www.mdpi.com/2072-6694/16/13/2457
34. Alectinib Approved as Adjuvant Treatment for ALK-Positive Non–Small Cell Lung Cancer, accessed July 30, 2025, https://ascopost.com/issues/may-10-2024/alectinib-approved-as-adjuvant-treatment-for-alk-positive-non-small-cell-lung-cancer/
35. Health-related quality of life (HRQoL) results for adjuvant alectinib vs chemotherapy in patients with resected ALK+ non-small cell lung cancer (NSCLC): Data from ALINA. | Journal of Clinical Oncology - ASCO Publications, accessed July 30, 2025, https://ascopubs.org/doi/10.1200/JCO.2024.42.16_suppl.8006
36. Alectinib in Resected ALK-Positive Non-Small-Cell Lung Cancer - PubMed, accessed July 30, 2025, https://pubmed.ncbi.nlm.nih.gov/38598794/
37. Alectinib Monotherapy Approved by the European Commission for ALK-Positive NSCLC, accessed July 30, 2025, https://oncoviews.com/2024/alectinib-monotherapy-approved-by-the-european-commission-for-alk-positive-nsclc/
38. ALINA Trial: Anticancer Activity of Alectinib Reported in Earlier-Stage, ALK-Positive NSCLC, accessed July 30, 2025, https://ascopost.com/issues/december-10-2023/alina-trial-anticancer-activity-of-alectinib-reported-in-earlier-stage-alk-positive-nsclc/
39. Alectinib shows benefit across genetic profiles in resected ALK-positive NSCLC, accessed July 30, 2025, https://dailyreporter.esmo.org/esmo-congress-2024/non-small-cell-lung-cancer/alectinib-shows-benefit-across-genetic-profiles-in-resected-alk-positive-nsclc
40. ALECENSA® (alectinib) HCP | Metastatic ALK+ NSCLC Treatment ..., accessed July 30, 2025, https://www.alecensa.com/hcp/metastatic.html
41. HIGHLIGHTS OF PRESCRIBING INFORMATION These ... - Genentech, accessed July 30, 2025, https://www.gene.com/download/pdf/alecensa_prescribing.pdf
42. Alecensa® (alectinib) - Information for Patients - Genentech, accessed July 30, 2025, https://www.gene.com/patients/medicines/alecensa
43. Targeted therapy treatment for ALK+ NSCLC - alecensa, accessed July 30, 2025, https://www.alecensa.com/hcp.html
44. Redefining Recovery: The Transformative Impact of the ALINA Trial on Adjuvant Therapy for ALK-Positive Non-Small Cell Lung Cancer - PubMed Central, accessed July 30, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC11367166/
45. FDA approves alectinib as adjuvant treatment for ALK-positive non-small cell lung cancer, accessed July 30, 2025, https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-alectinib-adjuvant-treatment-alk-positive-non-small-cell-lung-cancer
46. EMA Recommends Extension of Indications for Alectinib to Adjuvant Treatment of Resected ALK-positive NSCLC | ESMO, accessed July 30, 2025, https://www.esmo.org/oncology-news/ema-recommends-extension-of-indications-for-alectinib-to-adjuvant-treatment-of-resected-alk-positive-nsclc
47. Annotation of EMA Label for alectinib and ALK - PharmGKB, accessed July 30, 2025, https://www.pharmgkb.org/labelAnnotation/PA166182924
48. Adjuvant Alectinib Earns European Approval in Resectable ALK+ NSCLC - CancerNetwork, accessed July 30, 2025, https://www.cancernetwork.com/view/adjuvant-alectinib-earns-european-approval-in-resectable-alk-nsclc
49. alecensa, accessed July 30, 2025, https://www.alecensa.global/home.html
50. Comparative Efficacy and Safety of Lorlatinib and Alectinib for ALK-Rearrangement Positive Advanced Non-Small Cell Lung Cancer in Asian and Non-Asian Patients: A Systematic Review and Network Meta-Analysis - MDPI, accessed July 30, 2025, https://www.mdpi.com/2072-6694/13/15/3704
51. Lorlatinib Versus Crizotinib in Patients With Advanced ALK-Positive Non–Small Cell Lung Cancer: 5-Year Outcomes From the Phase III CROWN Study - ASCO Publications, accessed July 30, 2025, https://ascopubs.org/doi/10.1200/JCO.24.00581
52. Clinical Trials Using Alectinib - NCI, accessed July 30, 2025, https://www.cancer.gov/research/participate/clinical-trials/intervention/alectinib?pn=1
53. Alectinib continuation beyond progression in ALK-positive non-small cell lung cancer with alectinib-refractory - PubMed Central, accessed July 30, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC10891411/
54. A real-world retrospective study to assess efficacy and safety of alectinib as adjuvant therapy in IB-IIIB NSCLC patients harboring ALK rearrangement - Frontiers, accessed July 30, 2025, https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2024.1422035/full
55. Comparison of the effectiveness of alectinib versus crizotinib followed by alectinib in patients with ALK-positive advanced non-small-cell lung cancer in real-world setting and in the ALEX study - PubMed Central, accessed July 30, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC12082225/