Icotinib (DB11737): A Comprehensive Monograph on a First-Generation EGFR Tyrosine Kinase Inhibitor

Introduction and Executive Synthesis

Overview and Strategic Context

Icotinib, marketed under the trade name Conmana, is an orally available, small-molecule inhibitor of the epidermal growth factor receptor (EGFR) tyrosine kinase.[1] It belongs to the first generation of EGFR tyrosine kinase inhibitors (TKIs), a class of targeted therapies that has revolutionized the treatment of specific subsets of non-small cell lung cancer (NSCLC). The development history of Icotinib is unique and central to understanding its market position and clinical validation pathway. First synthesized in 2002, Icotinib was identified, optimized, and developed by Beta Pharma, a Chinese pharmaceutical company.[3] This "homegrown" origin distinguishes it from its primary first-generation competitors, gefitinib and erlotinib, which were developed by global pharmaceutical corporations. This regional focus shaped its initial clinical development and commercial strategy, leading to its emergence as a major therapeutic option within China and a case study in strategic pharmaceutical innovation.[4]

Core Indication and Therapeutic Niche

Icotinib is primarily indicated for the treatment of patients with locally advanced or metastatic NSCLC.[1] Its efficacy is most pronounced in patients whose tumors harbor activating mutations in the EGFR gene, most commonly deletions in exon 19 or the L858R point mutation in exon 21.[1] The regulatory journey of Icotinib began in China, where it was first approved by the State Food and Drug Administration (SFDA, now NMPA) in June 2011 for the treatment of patients with advanced NSCLC who had previously failed at least one platinum-based chemotherapy regimen.[1] Recognizing the superior efficacy of EGFR-TKIs in the first-line setting for mutation-positive patients, the indication was expanded in November 2014 to include first-line treatment for this population.[3] While its primary market remains China, early global ambitions were signaled in January 2014 when its developer, Beta Pharma, Inc., received a "May Proceed" letter from the United States Food and Drug Administration (US FDA) to conduct a Phase I study for EGFR-positive NSCLC.[1]

Executive Summary of Clinical Findings

The clinical value of Icotinib is supported by a robust and strategically designed clinical development program, which has progressively expanded its indications and solidified its therapeutic role. The evidence base is built upon several pivotal, large-scale clinical trials that have established its efficacy and safety across the spectrum of NSCLC treatment:

• Non-inferiority to Gefitinib: The foundational ICOGEN trial demonstrated that Icotinib was non-inferior to gefitinib in the second- and third-line treatment of advanced NSCLC, but with a statistically significant improvement in its safety profile, particularly a lower incidence of diarrhea.[12]
• Superiority to Chemotherapy: The CONVINCE trial established Icotinib as a superior first-line treatment option compared to standard platinum-based chemotherapy for patients with EGFR-mutant advanced NSCLC, showing a significant improvement in progression-free survival (PFS).[7]
• Benefit in Early-Stage Disease: The EVIDENCE trial demonstrated a profound and statistically significant improvement in disease-free survival (DFS) when Icotinib was used as an adjuvant therapy for patients with resected Stage II-IIIA EGFR-mutant NSCLC, compared to adjuvant chemotherapy.[15]
• Efficacy in Brain Metastases: In a landmark study, the BRAIN trial provided practice-changing evidence that Icotinib was superior to the long-standing standard of care, whole-brain radiotherapy (WBI), for the first-line management of patients with EGFR-mutant NSCLC and multiple brain metastases, offering substantially longer intracranial PFS with far less toxicity.[16]

Salient Insights and Report Roadmap

The development and clinical validation of Icotinib represent a sophisticated example of regional pharmaceutical strategy and meticulous lifecycle management. The drug successfully penetrated the highly competitive Chinese oncology market, ultimately capturing over a third of the market share for lung cancer therapies, by following a deliberate, stepwise approach.[4] The initial strategy de-risked development by aiming for non-inferiority against an established competitor (gefitinib) in a later-line setting, a common path for market entry.[13] This was bolstered by demonstrating a more favorable safety profile and leveraging a likely cost advantage, which facilitated rapid adoption.[13] Following this initial success, the clinical program was strategically expanded. The CONVINCE trial solidified its position in the valuable first-line setting by proving superiority over chemotherapy.[14] Subsequently, the EVIDENCE and BRAIN trials were not merely scientific inquiries but calculated moves to expand into new therapeutic areas (adjuvant therapy) and address high-unmet clinical needs (brain metastases).[15] The results of the BRAIN trial, in particular, provided Icotinib with a unique and powerful clinical advantage that distinguished it from other first-generation TKIs. This report will provide a comprehensive monograph on Icotinib, dissecting its molecular profile, preclinical pharmacology, pharmacokinetics, and extensive clinical trial data. It will offer a comparative analysis against its peers and a detailed assessment of its safety, dosing, and interactions, contextualizing the data within this strategic framework.

Molecular Profile and Preclinical Pharmacology

Chemical and Physical Properties

Icotinib is a synthetic organic compound belonging to the quinazoline class of molecules, a scaffold common to several first-generation EGFR inhibitors.[2] Its chemical structure is notable for the fusion of the quinazoline core with a tetraoxacyclododecane ring, a feature resembling a crown ether, which distinguishes it structurally from gefitinib and erlotinib.[2]

• Identifiers: The compound is cataloged under several key identifiers, including DrugBank ID DB11737, CAS Number 610798-31-7 (for the free base), and 1204313-51-8 (for the hydrochloride salt). Its Unique Ingredient Identifier (UNII) is 9G6U5L461Q.[1]
• Chemical Formula and Weight: The chemical formula for the free base is C22​H21​N3​O4​, corresponding to an average molecular weight of 391.427 g/mol and a monoisotopic mass of 391.1532 g/mol.[1] The clinically used hydrochloride salt has the formula C22​H22​ClN3​O4​ and a molecular weight of 427.89 g/mol.[20]
• Structure and Nomenclature: The formal IUPAC name is N-(3-ethynylphenyl)-7,8,10,11,13,14-hexahydro-tetraoxacyclododecino[2,3-g]quinazolin-4-amine.[19] It is also known by its development code, BPI-2009, and its trade name, Conmana.[1]
• Physical Properties: In its solid form, Icotinib is a light yellow or white-to-beige powder.[20] A critical physicochemical property is its solubility. It is soluble in organic solvents like dimethyl sulfoxide (DMSO) at concentrations around 1-2 mg/mL but is sparingly soluble in ethanol and is considered insoluble in water.[19] This poor aqueous solubility is a key determinant of its pharmaceutical formulation and influences its absorption characteristics. The compound is stable under proper storage conditions (e.g., 2-8°C, protected from light), with a reported shelf life of at least four years.[19]

Mechanism of Action

Icotinib exerts its antineoplastic effects through the targeted inhibition of the EGFR signaling pathway, which is a key driver of cell growth and proliferation in many cancers, including 40-80% of NSCLC cases.[7]

• Target Engagement: Icotinib is a potent, highly selective, and reversible inhibitor of the EGFR (also designated ErbB1 or HER1) tyrosine kinase.[1] It functions as an ATP-competitive inhibitor by binding to the adenosine triphosphate (ATP) binding pocket within the intracellular tyrosine kinase domain of the EGFR protein.[1] This reversible binding physically obstructs the access of ATP to its binding site.
• Inhibition of Downstream Signaling: The binding of ATP is the requisite first step for EGFR activation, which involves receptor dimerization and subsequent autophosphorylation of key tyrosine residues on its cytoplasmic tail.[8] By preventing ATP binding, Icotinib effectively blocks this autophosphorylation event.[1] This inhibition of the initial activation step prevents the recruitment and phosphorylation of downstream signaling proteins, thereby shutting down the entire signal transduction cascade. The key oncogenic pathways that are constitutively activated by mutant EGFR and subsequently inhibited by Icotinib include the RAS/RAF/MEK/ERK (MAPK) pathway, which is critical for cell cycle progression, and the PI3K/AKT/mTOR pathway, which promotes cell survival and inhibits apoptosis.[3] The ultimate cellular consequences of this pathway inhibition are a halt in unchecked cell proliferation, suppression of tumorigenesis, and the induction of programmed cell death (apoptosis) in cancer cells that are dependent on EGFR signaling.[8]

Pharmacodynamics and In Vitro/In Vivo Activity

Preclinical studies have extensively characterized the potency, selectivity, and antitumor activity of Icotinib, providing a strong scientific rationale for its clinical development.

• In Vitro Potency: Icotinib demonstrates potent enzymatic inhibition of EGFR kinase activity, with reported half-maximal inhibitory concentration (IC50​) values in the low nanomolar range, typically between 2 nM and 5 nM.[1] In cellular assays, it effectively blocks EGFR-mediated intracellular tyrosine phosphorylation in the A431 human epidermoid carcinoma cell line with an IC50​ of 45 nM.[19]
• Selectivity and Mutation Profile: The drug exhibits high selectivity for EGFR, showing minimal activity against other tyrosine kinases such as Abl and c-Src at concentrations up to 1,000 nM.[19] A crucial aspect of its activity profile is its ability to inhibit not only the wild-type form of EGFR but also the clinically important activating mutants that drive NSCLC. These include the common exon 19 deletions and the L858R and L861Q point mutations in exon 21.[1] Intriguingly, preclinical data also indicate that Icotinib possesses some inhibitory activity against the EGFR T790M mutation, the most common mechanism of acquired resistance to first-generation TKIs, with a reported 61% inhibition of enzymatic activity in vitro.[18] While this level of activity is not sufficient to provide durable clinical benefit against established T790M-positive tumors at standard doses, this preclinical signal may have contributed to the initial rationale for exploring whether higher drug concentrations, via dose escalation, could achieve a clinically meaningful level of T790M inhibition. However, subsequent clinical investigations, such as the INCREASE trial, pivoted to show that the primary benefit of dose escalation was in overcoming the intrinsically lower sensitivity of the L858R mutation, rather than reversing T790M-mediated resistance.[27] The complex landscape of resistance, which also involves bypass pathways like MET amplification, underscores why simply increasing the dose of a first-generation TKI is not a viable pan-resistance strategy.[29]
• Antiproliferative Activity: Icotinib demonstrates a broad spectrum of antitumor activity, showing particular efficacy against tumor cells that express high levels of EGFR.[1] It potently inhibits the growth of EGFR-mutant NSCLC cell lines, such as PC-9 (exon 19 deletion) and HCC827 (exon 19 deletion), with IC50​ values below 1,250 nM.[19] Furthermore, it has been shown to inhibit the migration of HCC827 cells and to significantly induce apoptosis in these cells at nanomolar concentrations.[19]
• In Vivo Efficacy: In preclinical animal models, orally administered Icotinib exhibits potent, dose-dependent antitumor effects in nude mice bearing a variety of human tumor xenografts.[1] The drug was demonstrated to be well-tolerated in these models at doses up to 120 mg/kg per day, with no significant mortality or body weight loss observed during treatment, indicating a favorable therapeutic window.[1]

Clinical Pharmacokinetics and Metabolism

Absorption, Distribution, Metabolism, and Excretion (ADME)

The pharmacokinetic profile of Icotinib has been well-characterized in clinical studies, revealing properties that are fundamental to its dosing schedule and potential for drug interactions.

• Absorption: Icotinib is formulated for oral administration in tablet form.[3] Following ingestion, it is rapidly absorbed from the gastrointestinal tract, with a median time to reach peak plasma concentration ( Tmax​) of approximately 3 to 4 hours.[6] The absolute oral bioavailability has been determined to be approximately 52%, indicating that about half of the administered dose reaches systemic circulation.[1] The presence of food can influence its absorption; a study noted that co-administration with a high-fat, high-calorie meal increased the overall drug exposure (AUC) by approximately 30%.[30]
• Distribution: Icotinib exhibits extensive distribution into bodily tissues, which is reflected by its large apparent volume of distribution (Vz​/F), calculated to be 115.00 ± 63.26 L.[1] In the bloodstream, Icotinib binds to human serum albumin (HSA), specifically at Sudlow's site I in subdomain IIA, forming drug-protein complexes that can influence its distribution and availability.[1]
• Metabolism: The drug undergoes extensive hepatic metabolism, with over 98% of the compound being converted into various metabolites.[3] The primary pathway for its biotransformation is through the cytochrome P450 (CYP) enzyme system. The major enzyme responsible for its metabolism is CYP3A4, with a minor contribution from CYP1A2.[1] This heavy reliance on CYP3A4 is the basis for many of its clinically significant drug-drug interactions. Despite extensive metabolism, studies in NSCLC patients have not identified any single metabolite that contributes more than 10% of the parent drug's plasma exposure, suggesting that Icotinib itself is the primary active moiety.[30]
• Excretion: The elimination of Icotinib and its metabolites occurs predominantly via the biliary-fecal route, with over 90% of the dose recovered in the feces. A much smaller fraction, approximately 9%, is excreted through the kidneys into the urine.[1] The systemic clearance ( CL/F) of the drug is calculated to be 13.30 ± 4.78 L/h.[2]

Pharmacokinetic Profile and Dosing Rationale

The pharmacokinetic parameters of Icotinib, particularly its half-life, are the primary determinants of its clinical dosing regimen.

• Half-Life: Icotinib is characterized by a relatively short elimination half-life (t1/2​). The median value is reported as 5.5 hours, with various clinical studies documenting a range between 5.3 and 8.1 hours.[1]
• Dosing Regimen: This short half-life is the single most critical pharmacokinetic feature defining Icotinib's clinical use. Standard pharmacological principles dictate that to maintain steady-state plasma concentrations above the therapeutic threshold, a drug should be administered at intervals that are approximately equal to its half-life. This directly mandates the three-times-daily (TID) dosing schedule (i.e., every 8 hours) that has been consistently used across all of Icotinib's pivotal clinical trials and is the basis for its approved dose of 125 mg TID.[9] This dosing frequency stands in stark contrast to the convenient once-daily (QD) administration of its main first-generation competitors, gefitinib and erlotinib. From a practical standpoint, a TID regimen presents a significant challenge to patient adherence in a real-world setting, which could potentially lead to missed doses, suboptimal drug exposure, and compromised efficacy compared to the highly monitored environment of a clinical trial. Conversely, this same pharmacokinetic property may underpin one of Icotinib's key clinical advantages: its favorable tolerability. The TID schedule results in more stable plasma concentrations throughout the day, avoiding the high peak concentrations ( Cmax​) associated with QD dosing of other TKIs. These high peaks are often linked to the intensity of concentration-dependent side effects like rash and diarrhea. Therefore, the inconvenient dosing schedule may be the very reason for its improved safety profile, creating a complex trade-off between convenience and tolerability that is a crucial aspect of its overall clinical profile.
• Dose-Exposure Relationship: Pharmacokinetic studies have revealed a non-linear relationship between the administered dose and the resulting drug exposure (AUC), particularly at higher dose levels.[10] This dose-proportionality appears to break down, with evidence of a saturation profile being observed at doses above 125 mg TID.[34] This phenomenon is likely attributable to the drug's poor aqueous solubility, which may lead to saturated absorption from the gastrointestinal tract at higher doses.[10]

Clinical Development and Efficacy in Advanced NSCLC

The clinical utility of Icotinib in advanced NSCLC has been established through a series of well-designed, large-scale Phase III trials. These studies have systematically evaluated its efficacy and safety against relevant comparators in different lines of therapy and patient populations, building a comprehensive evidence base that supports its use. The sequence of these trials reveals a deliberate and intelligent clinical development plan, progressing from a low-risk non-inferiority strategy to establish a market foothold, to a superiority trial to secure a first-line indication, and finally to practice-changing studies in areas of high unmet need.

Trial Name (Acronym)	ClinicalTrials.gov ID	Setting / Population	Comparator	Primary Endpoint	Key Result (Median Endpoint, Icotinib vs. Comparator)	Hazard Ratio (95% CI)	Key Publication
ICOGEN	NCT01040780	2nd/3rd-line advanced NSCLC (unselected)	Gefitinib	Progression-Free Survival (PFS)	4.6 months vs. 3.4 months	0.84 (0.67–1.05)	Shi Y, et al. Lancet Oncol. 2013 13
CONVINCE	NCT01719554	1st-line EGFRm+ advanced NSCLC	Cisplatin/Pemetrexed	Progression-Free Survival (PFS)	11.2 months vs. 7.9 months	0.61 (0.43–0.87)	Shi Y, et al. Ann Oncol. 2015 7
BRAIN	NCT01724801	1st-line EGFRm+ NSCLC with ≥3 brain metastases	Whole Brain Radiotherapy (WBI) +/- Chemo	Intracranial PFS	10.0 months vs. 4.8 months	0.56 (0.36–0.90)	Yang JJ, et al. Lancet Respir Med. 2017 16
EVIDENCE	NCT02448797	Adjuvant Stage II-IIIA EGFRm+ NSCLC	Vinorelbine/Cisplatin	Disease-Free Survival (DFS)	47.0 months vs. 22.1 months	0.36 (0.24–0.55)	He J, et al. Lancet Respir Med. 2021 15

The ICOGEN Trial: Establishing Non-Inferiority to Gefitinib (Second/Third-Line Setting)

The ICOGEN study (NCT01040780) was the foundational trial for Icotinib, strategically designed to secure its initial regulatory approval.

• Trial Design: This was a large, multicenter, randomized, double-blind, phase III non-inferiority trial conducted in China. It enrolled 399 patients with locally advanced or metastatic NSCLC who had progressed after at least one prior platinum-based chemotherapy regimen. Patients were randomized 1:1 to receive either Icotinib at a dose of 125 mg TID or the established standard-of-care TKI, gefitinib, at 250 mg QD.[12] The non-inferiority margin for the hazard ratio was set at 1.14.[13]
• Efficacy Results: The trial successfully met its primary endpoint. Icotinib was demonstrated to be non-inferior to gefitinib for progression-free survival. The median PFS was 4.6 months in the Icotinib arm compared to 3.4 months in the gefitinib arm (HR 0.84, 95% CI 0.67–1.05; p=0.13). The upper bound of the 95% confidence interval (1.05) was well below the pre-specified non-inferiority margin of 1.14, thus establishing non-inferiority.[12]
• Safety and Tolerability: A key finding of the ICOGEN trial was the superior safety profile of Icotinib. The incidence of any drug-related adverse event (AE) was significantly lower in the Icotinib group (61% of patients) compared to the gefitinib group (70% of patients; p=0.046). This difference was primarily driven by a statistically significant reduction in the rate of drug-related diarrhea (19% for Icotinib vs. 28% for gefitinib; p=0.033). The incidence of rash, the most common AE for both drugs, was also numerically lower in the Icotinib arm (41% vs. 49%).[13]
• Significance: The ICOGEN trial was a strategic success. By proving that Icotinib was "as good as" the market leader in efficacy but "better than" it in safety, the trial provided a compelling value proposition for clinicians and patients.[13] This evidence was instrumental in securing Icotinib's initial SFDA approval in 2011 and served as the critical first step in its campaign to capture significant market share.

The CONVINCE Trial: Proving Superiority as a First-Line Therapy

Following its success in the later-line setting, the CONVINCE trial was designed to move Icotinib into the more valuable first-line treatment space for the targeted population of EGFR-mutant patients.

• Trial Design: This was a Phase III, open-label, randomized trial that compared first-line Icotinib monotherapy against the standard-of-care chemotherapy regimen of cisplatin plus pemetrexed, followed by pemetrexed maintenance therapy. The study enrolled patients with stage IIIB/IV NSCLC whose tumors harbored an activating EGFR mutation.[7]
• Efficacy Results: The trial demonstrated the clear superiority of targeted therapy over chemotherapy in this population. Icotinib resulted in a statistically significant and clinically meaningful improvement in the primary endpoint of PFS. The median PFS for patients in the Icotinib group was 11.2 months, compared to only 7.9 months for those in the chemotherapy group (HR 0.61, 95% CI 0.43–0.87).[7] As is common in oncology trials where patients in the control arm can cross over to receive the effective experimental therapy upon progression, there was no significant difference in overall survival (OS) between the two groups.[7]
• Safety: The safety profile heavily favored Icotinib. Treatment-related AEs were significantly fewer and less severe in the Icotinib group. The most common AEs for Icotinib were low-grade rash (14.8%) and diarrhea (7.4%). In contrast, the chemotherapy arm was associated with high rates of typical chemotherapy-related toxicities, including nausea (45.9%), vomiting (29.2%), and hematologic toxicity like neutropenia (10.9%).[14]
• Significance: The CONVINCE trial was a crucial step in Icotinib's lifecycle management. Its results mirrored those of pivotal trials for gefitinib (IPASS) and erlotinib (OPTIMAL), confirming the class-wide benefit of EGFR-TKIs over chemotherapy in the first-line EGFR-mutant setting. This evidence was essential for securing the expanded first-line indication in China in 2014 and solidifying Icotinib's role as a standard of care.[7]

The BRAIN Trial: A Paradigm Shift in Managing Brain Metastases

Perhaps the most impactful study in the Icotinib clinical program, the BRAIN trial addressed a major unmet need in NSCLC: the management of brain metastases.

• Trial Design: The BRAIN trial (NCT01724801) was a multicenter, randomized, open-label, phase III trial conducted in EGFR-TKI-naïve patients with EGFR-mutant NSCLC who presented with at least three metastatic lesions in the brain. It directly compared the efficacy and safety of Icotinib (125 mg TID) against the long-established standard of care, WBI (30 Gy in 10 fractions), which could be combined with concurrent or sequential chemotherapy.[16]
• Efficacy Results: The trial produced practice-changing results. Icotinib was found to be dramatically superior to WBI, meeting its primary endpoint with a statistically significant improvement in intracranial PFS. The median intracranial PFS was 10.0 months for patients receiving Icotinib, more than double the 4.8 months observed in the WBI arm (HR 0.56, 95% CI 0.36–0.90; p=0.014).[16] Icotinib also significantly improved overall PFS (6.8 months vs. 3.4 months; HR 0.44) and led to a much higher intracranial objective response rate (65% vs. 37%; p=0.001).[17]
• Safety: The safety comparison was starkly in favor of Icotinib. Grade 3 or worse AEs were reported in only 8% of patients in the Icotinib group, compared to 38% of patients in the WBI plus chemotherapy group. WBI and chemotherapy were associated with significantly higher rates of fatigue, nausea, vomiting, and hematologic toxicities.[16]
• Significance: The BRAIN trial was the first phase III study to prospectively demonstrate the superiority of an EGFR-TKI over WBI for the initial management of multiple brain metastases in this specific patient population. These results challenged a decades-old treatment paradigm, establishing a new, more effective, and substantially less toxic standard of care. This provided Icotinib with a unique and powerful clinical advantage that no other first-generation TKI had demonstrated with such robust, randomized evidence, creating a defensible niche in the global therapeutic landscape.[16]

The INCREASE Trial: Dose Optimization for L858R Mutations

The INCREASE trial represents a sophisticated effort to personalize therapy by addressing the known differential sensitivity between the two most common EGFR mutations.

• Trial Design: This was a multicenter, randomized, phase II trial that specifically investigated whether a higher dose of Icotinib could improve outcomes for patients with the EGFR exon 21 L858R mutation, which is known to be intrinsically less sensitive to first-generation TKIs than exon 19 deletions. Treatment-naïve patients with the L858R mutation were randomized to receive either high-dose Icotinib (250 mg TID) or routine-dose Icotinib (125 mg TID). A third, non-randomized cohort of patients with exon 19 deletions receiving routine-dose Icotinib served as a benchmark for efficacy.[27]
• Efficacy Results: The dose-escalation strategy was successful. High-dose Icotinib led to a significant improvement in median PFS for patients with the L858R mutation, increasing it from 9.2 months in the routine-dose group to 12.9 months (HR 0.75, 95% CI 0.53–1.05). Critically, this brought the efficacy for the L858R mutation up to a level comparable to that observed in the more sensitive exon 19 deletion cohort, which had a median PFS of 12.5 months on the routine dose.[27] The objective response rate was also markedly higher in the high-dose L858R group compared to the routine-dose L858R group (73% vs. 48%).[27]
• Safety: The high-dose regimen was well-tolerated, with a similar incidence of grade 3/4 toxicities observed across the three treatment groups, demonstrating a wide therapeutic window for the drug.[27]
• Significance: The INCREASE trial is important as it provides prospective, randomized evidence supporting a mutation-specific dosing strategy for a first-generation TKI. It suggests that for patients with the less-sensitive L858R mutation, a higher dose of Icotinib can overcome this relative resistance and achieve outcomes similar to those seen in the more favorable exon 19 deletion population. This represents a step towards more nuanced, personalized medicine within the class of first-generation inhibitors.

Efficacy in Early-Stage and Other Investigational Settings

Beyond its established role in advanced disease, the clinical development program for Icotinib has explored its utility in the curative-intent setting of early-stage NSCLC, as well as in other novel therapeutic contexts.

The EVIDENCE Trial: Adjuvant Icotinib versus Chemotherapy

The EVIDENCE trial (NCT02448797) investigated whether the benefits of Icotinib could be extended to patients with earlier-stage disease following surgical resection.

• Trial Design: This was a large, multicenter, randomized, open-label, phase 3 trial that enrolled 322 patients with completely resected stage II-IIIA EGFR-mutant NSCLC. Patients were randomized 1:1 to receive either adjuvant Icotinib (125 mg TID) for a duration of two years or four cycles of the standard-of-care adjuvant chemotherapy regimen, vinorelbine plus cisplatin.[15]
• Efficacy Results: The trial reported a profound and highly statistically significant benefit for adjuvant Icotinib. The primary endpoint of disease-free survival (DFS) was dramatically improved in the Icotinib arm. The median DFS was 47.0 months for patients receiving Icotinib, more than double the 22.1 months seen in the chemotherapy arm (stratified HR 0.36, 95% CI 0.24–0.55; p<0.0001).[15] This translated to a 3-year DFS rate of 63.9% for Icotinib versus 32.5% for chemotherapy.[15] At the time of reporting, the overall survival data remained immature, with an equal number of deaths in both arms.[15]
• Safety: Consistent with its profile in advanced disease, Icotinib was significantly better tolerated than chemotherapy in the adjuvant setting. Treatment-related serious adverse events were rare in the Icotinib group, occurring in only 1% of patients, compared to 14% in the chemotherapy group.[15]
• Significance: The compelling DFS benefit and superior safety profile demonstrated in the EVIDENCE trial provide strong evidence to support the use of adjuvant Icotinib as a new standard of care for patients with resected, EGFR-mutant stage II-IIIA NSCLC. These results align with findings from similar trials of other EGFR-TKIs (e.g., osimertinib in the ADAURA trial), reinforcing the paradigm of using targeted therapy in the early-stage setting to delay or prevent disease recurrence.

Neoadjuvant and Consolidation Therapy

The breadth of Icotinib's investigation is further demonstrated by a portfolio of clinical trials exploring its role in other therapeutic settings, aiming to improve outcomes for patients with locally advanced disease.

• Neoadjuvant Therapy: Several trials have been initiated to evaluate the use of Icotinib prior to surgery (neoadjuvant therapy) with the goal of shrinking tumors to improve resectability and surgical outcomes. These studies are exploring Icotinib both as a single agent and in combination with chemotherapy. Examples include NCT01843647 (Icotinib plus cisplatin/vinorelbine), NCT03349203 (Icotinib as neoadjuvant and adjuvant therapy), and the ongoing NeoIpower study (NCT05104788), which is a Phase II trial of neoadjuvant Icotinib with chemotherapy for resectable stage II-IIIB NSCLC.[39]
• Consolidation Therapy: For patients with unresectable Stage III disease who have completed definitive chemoradiotherapy, the risk of recurrence is high. The NCT03396185 trial is a single-arm, prospective study evaluating Icotinib as a consolidation therapy in this specific population. Patients with unresectable, EGFR-mutant stage IIIA-IIIB lung adenocarcinoma receive Icotinib following the completion of chemoradiotherapy, with the primary objective of improving relapse-free survival.[9] This strategy aims to eradicate residual microscopic disease and prolong the period of disease control.
• Optimizing Adjuvant Duration: A key unanswered question in adjuvant TKI therapy is the optimal duration of treatment. The NCT01929200 trial was designed to address this directly by randomizing patients with resected stage II-IIIA NSCLC to receive either 1 year or 2 years of adjuvant Icotinib.[32] Separately, a three-arm study comparing 6 months of Icotinib, 12 months of Icotinib, and observation after adjuvant chemotherapy found that both the 6-month and 12-month durations provided a significant DFS and OS benefit compared to observation. However, extending treatment from 6 to 12 months did not confer any additional benefit, suggesting that a shorter duration may be sufficient while minimizing toxicity and cost.[42] These ongoing investigations are crucial for refining clinical practice and maximizing the benefit-risk ratio of adjuvant Icotinib.

Safety, Tolerability, and Risk Management

A comprehensive assessment of Icotinib's safety profile reveals a well-tolerated drug with a predictable and manageable spectrum of adverse events, which represents a key clinical advantage over both chemotherapy and some of its TKI peers.

Comprehensive Safety Profile

Data aggregated from numerous clinical trials and large-scale post-marketing studies have provided a clear picture of Icotinib's tolerability.

• Common Adverse Events: The most frequently reported adverse drug reactions (ADRs) are consistently skin-related events and gastrointestinal disturbances.[1] Specifically, rash (also described as acne-like rash or dermatitis) and diarrhea are the hallmark toxicities of the drug class, and Icotinib is no exception.[1] In a large, real-world study of 6,087 NSCLC patients, the most common ADRs were rash (17.4%) and diarrhea (8.5%).[43] In the adjuvant setting, where patients are generally healthier, the reported rates were higher but still predominantly low-grade: rash occurred in 83.7% of patients and diarrhea in 19.8%.[45]
• Severity: A defining feature of Icotinib's safety profile is that the vast majority of these common AEs are mild to moderate in severity (Grade 1 or 2 according to the Common Terminology Criteria for Adverse Events, CTCAE).[43] These events can typically be managed with supportive care (e.g., topical steroids or antibiotics for rash, loperamide for diarrhea) and rarely necessitate treatment discontinuation.[35] The incidence of severe (Grade 3 or higher) events is low across all studies.[42]
• Serious Adverse Events: Serious AEs related to Icotinib are infrequent. A particular concern for the EGFR-TKI class is the risk of interstitial lung disease (ILD) or pneumonitis, a potentially fatal toxicity. While cases of ILD have been reported with Icotinib, the incidence appears to be very low.[46] Notably, in the pivotal ICOGEN and EVIDENCE trials, no cases of ILD or treatment-related deaths were observed, highlighting its favorable profile in this regard.[13]

Long-Term Safety and Tolerability

An important and clinically valuable finding has emerged from the long-term observation of patients on Icotinib.

• Decreasing Incidence of ADRs Over Time: A large observational study involving 1,321 patients who received Icotinib for extended periods provided a unique insight into its long-term tolerability. The data showed that the frequency of ADRs significantly decreases after the initial phase of treatment. The overall incidence of any ADR was 65.4% within the first 6 months of therapy but fell sharply to 24.3% in patients treated for longer than 6 months. This trend was consistent for the most common side effects: the incidence of rash decreased from 31.8% to 16.4%, and the incidence of diarrhea decreased from 13.2% to 5.3%.[43] This is a powerful and clinically useful observation, as it is not a commonly reported or emphasized finding for other TKIs. It provides clinicians with a crucial data-driven counseling point to encourage patient adherence and persistence with therapy. By setting the evidence-based expectation that the initial side effects are likely to improve over time, physicians can better support patients through the most challenging early phase of treatment, thereby increasing the likelihood that they will remain on this life-prolonging therapy long enough to achieve the durable benefits seen in clinical trials.

Contraindications and Precautions

The use of Icotinib requires adherence to standard safety precautions for targeted therapies.

• Contraindications: The primary and absolute contraindication for Icotinib is a known history of severe hypersensitivity to the active substance or to any of the excipients in the tablet formulation.[6] Due to the potential for teratogenicity and harm to a developing fetus or nursing infant, Icotinib is not recommended for use in women who are pregnant or breastfeeding.[6]
• Precautions: Caution should be exercised when administering Icotinib to patients with pre-existing severe hepatic or renal impairment, as these conditions can affect drug metabolism and excretion, potentially leading to increased drug exposure and toxicity.[6] Given the known class risk of ILD, patients with a prior history of ILD or idiopathic pulmonary fibrosis were typically excluded from clinical trials and should be treated with extreme caution, if at all.[45]

Comparative Analysis and Therapeutic Positioning

To fully appreciate Icotinib's place in the therapeutic armamentarium for NSCLC, a direct comparison with its first-generation peers, gefitinib and erlotinib, is essential. This analysis reveals a drug with largely equivalent efficacy but a distinct and often more favorable safety profile.

Efficacy Metric	Icotinib	Gefitinib	Erlotinib	Source / Notes
Median PFS (months)	5.81	5.48	5.15	.48 Icotinib and Gefitinib significantly higher than Erlotinib (P<0.05).
Median Survival Time (MST, months)	12.58	13.26	13.52	.48 Erlotinib significantly longer than Gefitinib and Icotinib (P<0.05).
Overall Response Rate (ORR)	Equivalent	Equivalent	Equivalent	.48 Network meta-analysis found no significant difference.

Adverse Event	Icotinib	Gefitinib	Erlotinib	Source / Notes
Rash	Lowest Incidence	Intermediate	Highest Incidence	.48 Gefitinib vs. Icotinib OR=1.57 (P=0.002). Erlotinib vs. Gefitinib OR > 1.
Diarrhea	Highest Incidence	Intermediate	Lowest Incidence	.48 Trend analysis; ICOGEN showed lower diarrhea for Icotinib vs. Gefitinib (19% vs 28%).13
Nausea / Vomiting	Intermediate	Lowest Incidence	Highest Incidence	.48 Erlotinib vs. Gefitinib OR=2.0.
Fatigue	Highest Incidence	Lowest Incidence	Intermediate	.48 Trend analysis.

Note: The comparative safety data from the network meta-analysis in [48] shows some conflicting trends (e.g., for diarrhea) compared to direct head-to-head trials like ICOGEN. Head-to-head trial data is generally considered a higher level of evidence.

Icotinib vs. Gefitinib and Erlotinib

• Efficacy: A comprehensive network meta-analysis of randomized trials suggests that the three primary first-generation EGFR-TKIs—Icotinib, gefitinib, and erlotinib—possess broadly similar efficacy when it comes to key metrics like overall response rate (ORR) and disease control rate (DCR).[48] However, more nuanced differences emerge when examining survival endpoints. One large analysis found that Icotinib and gefitinib were associated with a significantly longer PFS compared to erlotinib (median PFS of 5.81 and 5.48 months vs. 5.15 months, respectively). Paradoxically, the same analysis reported that erlotinib was associated with the longest median survival time (MST) at 13.52 months, which was significantly longer than that for Icotinib (12.58 months).[48] This apparent disconnect between PFS and OS highlights the inherent limitations of cross-trial comparisons and network meta-analyses, as OS is heavily influenced by factors such as patient crossover and the type and efficacy of subsequent therapies received after progression. In the adjuvant setting, large-scale real-world data has shown comparable DFS among the three drugs, suggesting similar long-term disease control in early-stage disease.[50]
• Safety: Tolerability is where Icotinib most clearly distinguishes itself. In the direct head-to-head ICOGEN trial, Icotinib was significantly better tolerated than gefitinib, with lower rates of overall AEs and specifically diarrhea.[13] Broader meta-analyses support this favorable profile, consistently showing that Icotinib is associated with a lower frequency and severity of rash compared to both gefitinib and erlotinib.[48] This superior tolerability is a significant clinical differentiator, as it can improve patient quality of life and enhance adherence to long-term therapy.

Strategic Placement in Treatment Guidelines

In the contemporary landscape of NSCLC treatment, Icotinib is firmly established as a validated first-generation EGFR-TKI. Its position is naturally challenged by newer agents, including second-generation (e.g., afatinib) and third-generation (e.g., osimertinib) TKIs. These newer drugs offer improved efficacy, particularly the ability of osimertinib to potently inhibit the T790M resistance mutation and demonstrate superior CNS penetration and overall efficacy, which has led to its adoption as the preferred first-line agent in many international guidelines.

Despite this, Icotinib maintains a relevant and important therapeutic role due to several key factors:

1. Brain Metastases Niche: The robust, prospective, randomized data from the BRAIN trial gives Icotinib a unique and compelling indication for the first-line treatment of patients presenting with multiple brain metastases.[16] This provides a clear, evidence-based reason to choose Icotinib in this specific, challenging clinical scenario.
2. Cost-Effectiveness: As a domestically developed and manufactured drug in China, Icotinib offers a significant cost advantage over globally marketed TKIs.[18] This makes it a highly attractive and accessible option, particularly in health systems where cost is a primary consideration in treatment decisions.
3. Proven Adjuvant Benefit: The strong, positive data from the EVIDENCE trial establishes its role as an effective adjuvant therapy, an area where treatment decisions are often influenced by long-term tolerability and cost.[15]
4. Favorable Tolerability: Its well-documented favorable safety profile makes it a suitable option for patients who may be more susceptible to the toxicities of other TKIs.

Dosage, Administration, and Drug Interactions

Recommended Dosing and Administration

• Standard Dose: The approved, standard, and most widely studied dosage of Icotinib is 125 mg administered orally three times per day (TID), for a total daily dose of 375 mg.[3] Icotinib is supplied as 125 mg tablets.[27]
• High-Dose Regimens: The wide therapeutic window of Icotinib has allowed for the exploration of higher doses in specific clinical situations. The INCREASE trial successfully utilized a dose of 250 mg TID to improve outcomes in patients with the less-sensitive L858R mutation.[27] Furthermore, a Phase I dose-escalation study established a maximum tolerated dose (MTD) of 500 mg TID, with other studies exploring doses up to 375 mg TID for patients who progress on the standard dose.[10] Dose reduction is generally not recommended; instead, treatment interruption for up to 14 days is advised for managing Grade 3 or higher toxicities.[12]
• Administration: Icotinib tablets can be taken with or without food. However, patients should be aware that administration with a high-fat meal may increase drug exposure by approximately 30%.[6]

Interacting Drug/Class	Example Drugs	Effect on Icotinib / Other Drug	Clinical Recommendation
Strong CYP3A4 Inhibitors	Ketoconazole, Atazanavir, Aprepitant, Amiodarone, Diltiazem, Acalabrutinib, Boceprevir	Increases Icotinib plasma concentration and risk of toxicity.	Avoid combination if possible. If co-administration is necessary, monitor closely for Icotinib-related adverse events.
Strong CYP3A4 Inducers	Rifampicin, Apalutamide, Carbamazepine, Phenobarbital, St. John's Wort, Armodafinil	Decreases Icotinib plasma concentration, risking loss of efficacy.	Avoid combination. If unavoidable, monitor for reduced therapeutic effect of Icotinib.
CYP3A4-Modulating Biologics	Abatacept, Adalimumab, Anakinra, Bimekizumab	Can increase the metabolism of Icotinib, potentially reducing its concentration and efficacy.	Monitor for reduced therapeutic effect of Icotinib when initiating or discontinuing these agents.
Icotinib as an Inhibitor (Perpetrator)	Oxycodone, Apixaban, Atorvastatin, Aripiprazole, Alfentanil	Icotinib inhibits CYP3A4, increasing the concentration of co-administered CYP3A4 substrates.	Use with caution. Monitor for increased toxicity of the co-administered drug. Dose reduction of the substrate may be necessary.
Agents Causing Methemoglobinemia	Benzocaine, Articaine, Dapsone, Diphenhydramine, Ambroxol	Additive risk of developing methemoglobinemia.	Monitor for signs and symptoms of methemoglobinemia (e.g., cyanosis, headache, fatigue).

Clinically Significant Drug-Drug Interactions

Given that Icotinib is primarily metabolized by the CYP3A4 enzyme, it is highly susceptible to drug-drug interactions (DDIs) with agents that inhibit or induce this pathway.

• CYP3A4 Inhibitors: Co-administration of Icotinib with potent inhibitors of CYP3A4 can lead to a significant increase in Icotinib plasma concentrations, thereby elevating the risk of dose-dependent toxicities. Clinically important examples include azole antifungals (e.g., ketoconazole), certain protease inhibitors (e.g., atazanavir, boceprevir), and other drugs like aprepitant and amiodarone.[1] The concurrent use of these agents should be avoided. If unavoidable, patients must be monitored with increased vigilance for Icotinib-related adverse events.
• CYP3A4 Inducers: Conversely, co-administration with strong inducers of CYP3A4 can accelerate the metabolism of Icotinib, leading to substantially lower plasma concentrations and a high risk of therapeutic failure. Key examples include rifampicin, certain anticonvulsants (e.g., carbamazepine, phenobarbital), apalutamide, and the herbal supplement St. John's Wort.[1] These combinations should be avoided to ensure Icotinib maintains its efficacy.
• Icotinib as an Inhibitor/Inducer: Icotinib is not only a victim of DDIs but can also be the perpetrator. In vitro data and clinical studies have shown that Icotinib can inhibit the activity of CYP3A4.[53] This means it can increase the plasma concentrations of other drugs that are substrates of this enzyme. For example, it has been shown to inhibit the metabolism of the opioid analgesic oxycodone, necessitating dose reconsideration when the two are used together.[53] Caution is also warranted when co-administering Icotinib with other sensitive CYP3A4 substrates like apixaban, atorvastatin, and certain benzodiazepines.[1]
• Other Interactions: A specific pharmacodynamic interaction has been noted with agents that can cause methemoglobinemia. The risk of this rare but serious condition may be increased when Icotinib is combined with drugs like local anesthetics (benzocaine, articaine) or dapsone.[1]

Conclusion and Future Directions

Final Synthesis

Icotinib has firmly established itself as an effective, safe, and valuable first-generation EGFR tyrosine kinase inhibitor for the treatment of non-small cell lung cancer. Its journey from a domestically developed candidate to a market-leading therapy in China is a testament to a well-executed and highly strategic clinical development program. This program successfully de-risked its entry, proved its superiority over the existing standard of care, and carved out unique, evidence-based niches that differentiate it from its competitors. The comprehensive body of evidence defines Icotinib by three core attributes: efficacy that is comparable to its first-generation peers, a consistently more favorable safety and tolerability profile, and unprecedented, practice-changing data supporting its use in the challenging setting of multiple brain metastases.

Impact on the Therapeutic Landscape

The story of Icotinib is significant not only as a clinical success but also as a commercial and strategic one. It serves as a powerful case study for how a regional pharmaceutical company can effectively develop a drug, prove its value against established local standards, and then generate unique, globally relevant data to create a defensible and valuable market position. Clinically, its most profound and lasting impact may be its role in shifting the treatment paradigm for patients with EGFR-mutant NSCLC who present with brain metastases. The BRAIN trial provided the high-level evidence needed to move away from the toxic and less effective standard of whole-brain radiotherapy toward a more effective and far better-tolerated targeted oral therapy, directly improving patient outcomes and quality of life.

Future Directions

Despite its well-established role, several questions regarding the optimal use of Icotinib remain, and new avenues for research are emerging.

• Outstanding Questions: The final overall survival data from the pivotal EVIDENCE and BRAIN trials are eagerly awaited. While the DFS and intracranial PFS benefits are clear, confirmation of a long-term survival advantage will be crucial for solidifying its place in treatment guidelines. Furthermore, the optimal duration of adjuvant therapy is still an area of active investigation, with studies suggesting that shorter durations may provide similar benefits with less toxicity and cost, a question with significant health-economic implications.[32]
• Future Research: The future of Icotinib, like that of all first-generation TKIs, will likely lie in intelligent combination strategies designed to overcome or delay the onset of acquired resistance. Investigating combinations with other targeted agents, such as anti-angiogenic drugs (e.g., bevacizumab) or inhibitors of bypass pathways (e.g., MET inhibitors), is a logical next step. Another critical and currently unexplored area is the potential role of Icotinib in combination with immunotherapy, which has become a cornerstone of treatment for EGFR wild-type NSCLC. Finally, further investigation into its efficacy in patients with less common EGFR mutations is warranted to better define its full spectrum of activity.[29] These future studies will be essential to continue maximizing the clinical value of this important therapeutic agent.

Works cited

1. go.drugbank.com, accessed August 6, 2025, https://go.drugbank.com/drugs/DB11737
2. Icotinib | C22H21N3O4 | CID 22024915 - PubChem, accessed August 6, 2025, https://pubchem.ncbi.nlm.nih.gov/compound/22024915
3. Icotinib - Wikipedia, accessed August 6, 2025, https://en.wikipedia.org/wiki/Icotinib
4. BPI-2009H (Icotinib) - Beta Pharma, accessed August 6, 2025, http://betapharma.com/pipeline_item/bh-2009h/
5. Icotinib Hydrochloride - Drug Targets, Indications, Patents - Patsnap Synapse, accessed August 6, 2025, https://synapse.patsnap.com/drug/f2b21c4b3f7f48d687c4e70209b461bc
6. What is Icotinib Hydrochloride used for? - Patsnap Synapse, accessed August 6, 2025, https://synapse.patsnap.com/article/what-is-icotinib-hydrochloride-used-for
7. Icotinib improves progression free survival in epidermal growth factor receptor positive non-small cell lung cancer patients, accessed August 6, 2025, https://tcr.amegroups.org/article/view/18592/html
8. What is the mechanism of Icotinib Hydrochloride? - Patsnap Synapse, accessed August 6, 2025, https://synapse.patsnap.com/article/what-is-the-mechanism-of-icotinib-hydrochloride
9. Icotinib as Consolidation Therapy After Chemoradiotherapy in EGFR-Mutant Stage IIIA-IIIB Non-small Cell Lung Cancer | ClinicalTrials.gov, accessed August 6, 2025, https://clinicaltrials.gov/study/NCT03396185
10. A Phase I Study of the Safety and Pharmacokinetics of Higher-Dose ..., accessed August 6, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC5189627/
11. Efficacy and safety of icotinib in the treatment of advanced EGFR mutation-positive nonsmall cell lung cancer: A meta-analysis of randomized controlled trials - PubMed Central, accessed August 6, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC9726281/
12. The Efficacy and Safety of Icotinib in Patients with Advanced Non-Small Cell Lung Cancer Previously Treated with Chemotherapy: A Single-Arm, Multi-Center, Prospective Study, accessed August 6, 2025, https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0142500
13. Icotinib versus gefitinib in previously treated advanced non-small ..., accessed August 6, 2025, https://pubmed.ncbi.nlm.nih.gov/23948351/
14. Icotinib vs. Chemotherapy in EGFR-Positive Lung Adenocarcinoma - JNCCN 360, accessed August 6, 2025, https://jnccn360.org/non-small-cell-lung-cancer/medical-literature/icotinib-versus-chemotherapy-in-egfr-positive-lung-adenocarcinoma/
15. Icotinib versus chemotherapy as adjuvant treatment for stage II-IIIA ..., accessed August 6, 2025, https://pubmed.ncbi.nlm.nih.gov/34280355/
16. Icotinib Versus Whole-Brain Irradiation in Patients With EGFR-mutant Non-Small-Cell Lung Cancer and Multiple Brain Metastases (BRAIN): A Multicentre, Phase 3, Open-Label, Parallel, Randomised Controlled Trial - PubMed, accessed August 6, 2025, https://pubmed.ncbi.nlm.nih.gov/28734822/
17. Icotinib versus whole-brain irradiation in patients with EGFR-mutant ..., accessed August 6, 2025, https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(17)30262-X/fulltext
18. Icotinib Is an Active Treatment of Non-Small-Cell Lung Cancer: A Retrospective Study, accessed August 6, 2025, https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0095897
19. Icotinib (BPI 2009H, CAS Number: 610798-31-7) | Cayman Chemical, accessed August 6, 2025, https://www.caymanchem.com/product/30093/icotinib
20. Icotinib hydrochloride | BPI-2009 | CAS#1204313-51-8 | 610798-31-7 | MedKoo Biosciences, accessed August 6, 2025, https://www.medkoo.com/products/4671
21. Icotinib hydrochloride | DrugBank Online, accessed August 6, 2025, https://go.drugbank.com/salts/DBSALT002060
22. Icotinib, 610798-31-7, 98 (HPLC) Sigma-Aldrich, accessed August 6, 2025, https://www.sigmaaldrich.com/US/en/product/sigma/sml3725
23. Icotinib | EGFR inhibitor | Buy from Supplier AdooQ®, accessed August 6, 2025, https://www.adooq.com/icotinib.html
24. PRODUCT INFORMATION - Cayman Chemical, accessed August 6, 2025, https://cdn.caymanchem.com/cdn/insert/30093.pdf
25. en.wikipedia.org, accessed August 6, 2025, https://en.wikipedia.org/wiki/Icotinib#:~:text=Mechanism%20of%20action,-Icotinib%20is%20a&text=By%20blocking%20the%20binding%20of,transduction%20cascade%20that%20initiates%20mitosis.
26. Cellular mechanisms of action of icotinib. Icotinib selectively binds... - ResearchGate, accessed August 6, 2025, https://www.researchgate.net/figure/Cellular-mechanisms-of-action-of-icotinib-Icotinib-selectively-binds-to-the-ATP-binding_fig1_322954568
27. Routine-Dose and High-Dose Icotinib in Patients with Advanced Non–Small Cell Lung Cancer Harboring EGFR Exon 21-L858R Mutation: the Randomized, Phase II, INCREASE Trial - AACR Journals, accessed August 6, 2025, https://aacrjournals.org/clincancerres/article/26/13/3162/82574/Routine-Dose-and-High-Dose-Icotinib-in-Patients
28. Routine-Dose and High-Dose Icotinib in Patients with Advanced Non-Small Cell Lung Cancer Harboring EGFR Exon 21-L858R Mutation: the Randomized, Phase II, INCREASE Trial - PubMed, accessed August 6, 2025, https://pubmed.ncbi.nlm.nih.gov/32060099/
29. Potential mechanism of primary resistance to icotinib in patients with advanced non–small cell lung cancer harboring uncommon mutant epidermal growth factor receptor: A multi‐center study, accessed August 6, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC7004544/
30. Clinical pharmacokinetics, safety, and preliminary efficacy evaluation of icotinib in patients with advanced non-small cell lung cancer - PubMed, accessed August 6, 2025, https://pubmed.ncbi.nlm.nih.gov/26162563/
31. Study Details | Icotinib or Whole Brain Irradiation in EGFR-mutant ..., accessed August 6, 2025, https://www.clinicaltrials.gov/study/NCT01724801
32. Study Details | Icotinib as Adjuvant Therapy in Treating Non-small-cell Lung Cancer Patients With Positive EGFR Mutation | ClinicalTrials.gov, accessed August 6, 2025, https://www.clinicaltrials.gov/study/NCT01929200
33. Icotinib as Adjuvant Therapy Compared With Standard Chemotherapy in Stage II-IIIA NSCLC With EGFR-mutation (EVIDENCE) - ClinicalTrials.gov, accessed August 6, 2025, https://www.clinicaltrials.gov/study/NCT02448797
34. Routine-Dose and High-Dose Icotinib in Patients with Advanced Non–Small Cell Lung Cancer Harboring EGFR Exon 21-L858R Mutation - AACR Journals, accessed August 6, 2025, https://aacrjournals.org/clincancerres/article-pdf/26/13/3162/2061426/3162.pdf
35. Efficacy and safety of icotinib as first-line therapy in patients with | OTT - Dove Medical Press, accessed August 6, 2025, https://www.dovepress.com/efficacy-and-safety-of-icotinib-as-first-line-therapy-in-patients-with-peer-reviewed-fulltext-article-OTT
36. Phase I trial of icotinib combined with whole brain radiotherapy for EGFR-mutated non-small cell lung cancer patients with brain metastases. - ASCO, accessed August 6, 2025, https://www.asco.org/abstracts-presentations/ABSTRACT125650
37. A meta-analysis for the efficacy and safety of icotinib combined with radiotherapy in treating brain metastases of non-small cell lung cancer - PMC, accessed August 6, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC10489315/
38. Icotinib and whole brain radiotherapy (WBRT) for patients with brain metastases from non-small cell lung cancer (NSCLC): Preliminary results of a phase II study. - ASCO Publications, accessed August 6, 2025, https://ascopubs.org/doi/10.1200/jco.2013.31.15_suppl.e19073
39. Icotinib Unknown Status Phase 2 Trials for Non-Small Cell Lung Cancer (NSCLC) Treatment - DrugBank, accessed August 6, 2025, https://go.drugbank.com/drugs/DB11737/clinical_trials?conditions=DBCOND0034130&phase=2&purpose=treatment&status=unknown_status
40. Icotinib Unknown Status Phase 2 Trials for EGF-R Negative Non-Small Cell Lung Cancer Treatment - DrugBank, accessed August 6, 2025, https://go.drugbank.com/drugs/DB11737/clinical_trials?conditions=DBCOND0144988&phase=2&purpose=treatment&status=unknown_status
41. A Study of Icotinib With Chemotherapy as Neoadjuvant Therapy for Patients With EGFRm Positive Resectable Non-Small Cell Lung Cancer | ClinicalTrials.gov, accessed August 6, 2025, https://clinicaltrials.gov/study/NCT05104788
42. Adjuvant icotinib of 12 months or 6 months versus observation following adjuvant chemotherapy for resected EGFR-mutated stage, accessed August 6, 2025, https://ascopubs.org/doi/pdf/10.1200/JCO.2024.42.16_suppl.8004
43. Long-term safety of icotinib in patients with non-small cell lung cancer: a retrospective, real-world study - Journal of Thoracic Disease, accessed August 6, 2025, https://jtd.amegroups.org/article/view/35960/html
44. Long-term safety of icotinib in patients with non-small cell lung cancer: a retrospective, real-world study - AME Publishing Company, accessed August 6, 2025, https://cdn.amegroups.cn/journals/pbpc/files/journals/2/articles/35960/public/35960-PB10-7543-R3.pdf
45. Survival benefit and toxicity profile of adjuvant icotinib for patients with EGFR mutation-positive non-small cell lung carcinoma: a retrospective study, accessed August 6, 2025, https://tlcr.amegroups.org/article/view/47451/html
46. Icotinib as Adjuvant Treatment for Stage II-IIIA Lung Adenocarcinoma Patients with EGFR Mutation (ICWIP Study): Study Protocol for a Randomised Controlled Trial - PMC - PubMed Central, accessed August 6, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC7306474/
47. Long-term safety of icotinib in patients with non-small cell lung cancer: a retrospective, real-world study, accessed August 6, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC7139014/
48. Comparison of effectiveness and adverse effects of gefitinib ..., accessed August 6, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC5658684/
49. Network Meta-Analysis of Erlotinib, Gefitinib, Afatinib and Icotinib in Patients with Advanced Non-Small-Cell Lung Cancer Harboring EGFR Mutations | PLOS One - Research journals, accessed August 6, 2025, https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0085245
50. Comparison of first-generation EGFR-TKIs (gefitinib, erlotinib, and icotinib) as adjuvant therapy in resected NSCLC patients with sensitive EGFR mutations - PubMed Central, accessed August 6, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC8674600/
51. High Dose Versus Routine Dose Icotinib in Advanced Non-small Cell Lung Cancer Patients With Stable Disease | ClinicalTrials.gov, accessed August 6, 2025, https://www.clinicaltrials.gov/study/NCT02027090
52. High Dose Icotinib in Advanced Non-small Cell Lung Cancer With EGFR 21 Exon Mutation (INCREASE) - ClinicalTrials.gov, accessed August 6, 2025, https://clinicaltrials.gov/study/NCT02404675
53. The effect of icotinib or apatinib on the pharmacokinetic profile of oxycodone in rats and the underlying mechanism - PeerJ, accessed August 6, 2025, https://peerj.com/articles/16601.pdf
54. The effect of icotinib or apatinib on the pharmacokinetic profile of oxycodone in rats and the underlying mechanism, accessed August 6, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC10712305/
55. The effect of icotinib or apatinib on the pharmacokinetic profile of oxycodone in rats and the underlying mechanism - PeerJ, accessed August 6, 2025, https://peerj.com/articles/16601/