A Phase II Study of Aumolertinib Combined With Phased Chemotherapy for Treatment-Naïve EGFR L858R-Mutated Lung Adenocarcinoma (ACCEL Trial)
A Phase II Study of Aumolertinib Combined With Phased Chemotherapy for Treatment-Naïve EGFR L858R-Mutated Lung Adenocarcinoma (ACCEL Trial)
Background: While third-generation EGFR tyrosine kinase inhibitors (TKI) like aumolertinib have significantly improved outcomes for patients with advanced lung adenocarcinoma, those harboring the L858R mutation still experience inferior prognosis compared to those with exon 19 deletions. Recent evidence suggests that combining TKIs with chemotherapy improves progression-free survival (PFS), but universal application of this combination exposes all patients to cytotoxic toxicity, even those who might thrive on TKI monotherapy alone. Circulating cell-free DNA (cfDNA) and minimal residual disease monitoring offer a dynamic window to identify which patients truly require treatment intensification.
Objectives: The primary objective is to evaluate the predictive value of early molecular response by determining the association between the change in EGFR mutant allele fraction in cfDNA after a 6-week aumolertinib lead-in induction phase (T1) and a 4-cycle combination chemotherapy (T2) with clinical PFS. Secondary objectives include assessing overall response rates (ORR), disease control rate (DCR), safety, and the dynamics of EGFR mutant allele fraction and circulating immune cell profiles.
Study Design: This is a prospective, single-arm, multicenter, phase II clinical trial enrolling 50 evaluable patients. The study utilizes a three-phase treatment framework:
Endpoints: The primary efficacy endpoint is Progression-Free Survival (PFS). Molecular efficacy will be measured via the Molecular Clearance Rate (MCR) and Molecular Response Rate (MRR) at baseline (T0), post-induction (T1), and post-chemotherapy (T2). Safety will be graded according to CTCAE v5.0.
Conclusion and Significance: This trial aims to establish a molecularly driven framework for personalized lung cancer management, seeking to maximize efficacy for high-risk patients while providing the foundation to spare molecular responders from unnecessary chemotherapy in the future. The results will serve as the base for the design of future confirmatory phase III trials.
Background Lung cancer remains the leading cause of oncological mortality worldwide, representing a formidable challenge to global public health systems (1,2). Within the broad classification of lung malignancies, non-small cell lung cancer (NSCLC) accounts for the vast majority of cases, with lung adenocarcinoma (LUAD) being the most frequent histological subtype diagnosed in clinical practice. The molecular characterization of LUAD has fundamentally changed the therapeutic approach, shifting the focus from broad cytotoxic treatments to personalized medicine based on specific genomic alterations. Among these, mutations in the epidermal growth factor receptor (EGFR) gene stand out as one of the most significant and actionable therapeutic targets (3,4). The prevalence of EGFR mutations exhibits a striking geographic and ethnic disparity; while occurring in approximately 10-15% of Western populations, these mutations are found in nearly 50% of Asian patients with LUAD (5). This high frequency in the Asian population necessitates a specialized focus on optimizing treatment strategies for this demographic. Historically, the identification of these mutations served as the catalyst for the development of targeted therapies that have significantly improved survival outcomes. Despite these advancements, lung cancer continues to impose a heavy burden due to its aggressive nature and the eventual development of resistance to current therapies. Understanding the specific genomic landscape of LUAD in the Asian context is not merely an academic exercise but a clinical necessity to improve the prognosis of millions of patients. As we look toward the future of oncology, refining our approach to EGFR-mutant disease remains a top priority to further reduce the mortality rates associated with this devastating illness.
The treatment of EGFR-mutant LUAD has undergone a remarkable transformation since the discovery of sensitizing mutations in 2004 (6). The introduction of first-generation EGFR tyrosine kinase inhibitors (TKIs), such as gefitinib and erlotinib, established a new paradigm by demonstrating superior efficacy and better tolerability compared to platinum-based chemotherapy in the first-line setting. These agents work by reversibly binding to the ATP-binding pocket of the EGFR kinase domain, thereby inhibiting downstream signaling pathways that drive tumor cell proliferation. However, most patients eventually experience disease progression, often due to the acquisition of the T790M resistance mutation (7). Second-generation TKIs, including afatinib and dacomitinib, were developed as irreversible inhibitors designed to provide more potent blockade of the ErbB family; while effective, their clinical utility was frequently limited by dose-related toxicities such as diarrhea and skin rash. The third-generation TKI, osimertinib, represented a major breakthrough by selectively targeting both sensitizing mutations and the T790M resistance mutation while sparing wild-type EGFR (8). The FLAURA trial demonstrated that osimertinib significantly extended progression-free survival and overall survival compared to first-generation agents (9), establishing it as the preferred first-line standard of care for treatment-naïve advanced LUAD. Nowadays, there are several third-generation EGFR-TKIs, including agents such as osimertinib, lazertinib, aumolertinib, and furmonertinib (10). While the clinical response to these agents is initially robust, the inevitable development of resistance and the heterogeneity of patient outcomes indicate that there is significant room for therapeutic optimization. To address these limitations, recent research has focused on intensifying frontline treatment through combination strategies. One major approach involves the addition of platinum-based chemotherapy to third-generation TKIs, a strategy validated by the FLAURA2 trial (11), which demonstrated a significant extension in progression-free survival compared to TKI monotherapy. Another evolving paradigm is the use of bispecific antibodies, such as amivantamab, which targets both EGFR and MET pathways. The MARIPOSA study highlighted the potential of combining amivantamab with lazertinib to provide a more comprehensive blockade of oncogenic signaling, thereby delaying the onset of resistance (12). These advancements suggest that while monotherapy remains a potent tool, the future of EGFR-mutant LUAD management lies in identifying the most effective combination regimens to further prolong patient survival.
Aumolertinib is an orally administered, irreversible third-generation EGFR-TKI specifically engineered to address the limitations of earlier-generation therapies. Developed with a focus on high selectivity, the drug targets common sensitizing mutations, such as exon 19 deletions and the L858R point mutation, as well as the resistance mutation. A defining pharmacological feature of aumolertinib is its ability to irreversibly bind to the kinase domain while sparing the wild-type form of the receptor. This selectivity is critical for clinical practice, as it significantly reduces the incidence of off-target toxicities-such as severe skin rash and diarrhea-that frequently led to dose interruptions or discontinuations with first- and second-generation inhibitors (13). The clinical efficacy of aumolertinib was established through the pivotal phase 3 AENEAS trial (14). In this study, treatment-naïve patients receiving aumolertinib achieved a median progression-free survival of 19.3 months, a result that was not only significantly superior to the 9.9 months observed with gefitinib but also remarkably consistent with the outcomes of other leading third-generation TKIs like osimertinib. Beyond systemic control, aumolertinib and its active N-desmethyl metabolite, HAS-719, demonstrate potent blood-brain barrier penetration (13). This characteristic is vital for the management of NSCLC, where central nervous system (CNS) metastases represent a major cause of morbidity and treatment failure. Clinical data from both the AENEAS and APOLLO trials (14,15) confirmed that aumolertinib provides robust intracranial activity, with objective response rates and progression-free survival in patients with brain metastases comparable to those in the overall study populations.
Aumolertinib also presents a unique safety profile. While it shares some class-wide side effects, such as a manageable risk of QT interval prolongation and rare instances of interstitial lung disease, it is frequently associated with elevations in blood creatinine phosphokinase. In the AENEAS trial, increased CPK was the most frequent grade ≥ 3 adverse event in the aumolertinib arm. However, these elevations are typically asymptomatic and rarely lead to permanent treatment discontinuation. Importantly, the incidence of rash and diarrhea was lower with aumolertinib than with gefitinib, reflecting its superior selectivity over wild-type.
Expanding its clinical utility, recent phase II evidence has investigated the role of aumolertinib as a backbone for combination therapy. In a study evaluating first-line aumolertinib plus pemetrexed and carboplatin, the combination achieved a striking objective response rate (ORR) of 91.2% and a median progression-free survival of 28.0 months (16). This intensified approach did not yield new safety signals, and the toxicity profile remained consistent with the established side effects of the individual agents. The most common high-grade adverse events in the combination setting were hematological, such as decreased neutrophil counts, which are primarily attributed to the chemotherapy component. Furthermore, exploratory analyses in these trials highlighted the prognostic value of circulating tumor DNA (ctDNA) clearance, where patients achieving molecular clearance within the first few cycles of treatment experienced significantly prolonged progression-free survival compared to those who did not. These findings underscore the potential of aumolertinib not only as a potent monotherapy but as a safe and effective foundation for precision-based combination strategies aimed at maximizing the depth of response in EGFR-mutant NSCLC.
While EGFR mutations are collectively recognized as primary oncogenic drivers in lung adenocarcinoma, it is increasingly evident that these genomic alterations are not created equal. The two most prevalent variants, exon 19 deletions (Ex19del) and the L858R point mutation in exon 21, account for approximately 90% of all sensitizing EGFR mutations. Despite their shared classification, these variants exhibit distinct biochemical properties and clinical behaviors. Specifically, the L858R mutation has been consistently associated with poorer treatment outcomes compared to Ex19del across multiple generations of tyrosine kinase inhibitors. Structural analyses reveal that the L858R substitution leads to a less stable active conformation of the kinase domain (17), resulting in a lower binding affinity for TKIs than that observed with Ex19del. This reduced sensitivity manifests clinically as shorter progression-free survival and lower response rates when these patients are treated with TKI monotherapy.
Furthermore, the L858R subgroup appears to harbor greater genomic instability and a higher frequency of co-occurring mutations, such as TP53 alterations, which further compromise the efficacy of targeted agents (18). To mitigate this inferior prognosis, intensified treatment strategies have been explored. Emerging evidence from large-scale clinical trials and smaller phase II studies indicates that the addition of chemotherapy may be particularly beneficial for this "high-risk" subgroup. Interestingly, recent data suggest that combination therapy can potentially close the gap in efficacy, improving the survival outcomes of L858R patients to a level comparable to those historically seen in Ex19del patients. These observations emphasize the necessity of moving beyond a "one-size-fits-all" approach and developing more aggressive, tailored regimens for patients harboring the L858R mutation to overcome their inherent resistance and achieve deeper clinical responses.
While intensifying first-line treatment through combination therapy appears to be a feasible approach for improving outcomes in EGFR-mutated disease, it introduces significant clinical and economic challenges that cannot be ignored. Evidence from large-scale trials indicates that the survival benefits of adding chemotherapy to third-generation TKIs are not distributed equally across the entire patient population. In fact, data from the FLAURA2 study showed that while the combination improved progression-free survival, a substantial proportion of patients in the monotherapy arm remained progression-free at 24 months (41% vs. 57% in the combination arm), suggesting that roughly 16% of the population drives the incremental benefit (11). Despite this disproportionate gain, the entire cohort is exposed to the increased toxicity inherent in cytotoxic regimens. In fact, ~40% of the population will simply suffer from the toxicities without obtaining any benefit. Common high-grade adverse events, particularly hematological toxicities such as neutropenia and anemia, as well as gastrointestinal intolerance and peripheral neuropathy, are significantly more frequent in combination arms than in monotherapy groups. For instance, earlier trials observed that the rate of grade 3 or 4 drug-related adverse events more than doubled with the addition of chemotherapy (42% vs. 19%), leading to a higher rate of dose interruptions and a potential reduction in overall quality of life (19). In fact, in FLUAR2 trial, for example, the median treatment duration of chemotherapy and osimertinib in the combination arm were 8.3 months and 30.5 months, respectively, suggesting that many patients could not tolerate the chemotherapy side effect and withdrew from the chemotherapy but maintained osimertinib in the trial (20).
Beyond the physical toll on patients, universal combination therapy imposes a substantial financial burden. This impact is felt both by individual patients through increased out-of-pocket expenses and by the broader healthcare system through the heightened budget impact on national health insurance system. Recent economic analyses highlight that the total all-cause healthcare costs per patient per month for EGFR-mutated advanced NSCLC are already high (21), with costs increasing further as patients move through successive lines of therapy. The addition of intravenous chemotherapy-requiring not only treatment itself, but also frequent hospital visits, specialized nursing care, and management of infusion-related complications-adds a significant layer of expense compared to oral TKI monotherapy (22). In systems with capped medical budgets, such as national health insurance programs, the cost-effectiveness of treating 100% of patients to benefit only a small subset is a major concern. Consequently, a more precise approach is warranted to identify specific biomarkers that can distinguish those who require early chemotherapy from those who can safely avoid its associated risks and costs.
The utilization of circulating cell-free DNA (cfDNA) as a non-invasive biomarker has fundamentally redefined the monitoring of treatment response in solid tumors. In the context of EGFR-mutated LUAD, cfDNA-specifically the portion derived from the tumor (ctDNA)-provides a real-time assessment of the systemic tumor burden and the treatment response. One of the most significant applications of this technology is the detection of minimal residual disease (MRD), which refers to the presence of residual cancer clones that remain below the threshold of conventional radiological imaging. The identification of MRD through longitudinal cfDNA sampling has been shown to precede radiological progression by several months, providing a critical window for therapeutic adjustment. Clinical evidence from post-hoc analyses of the FLAURA and SWOG S1403 trials confirms that the failure to achieve early molecular clearance of EGFR mutations in the plasma is a strong predictor of shorter progression-free survival and overall survival (23,24). By concentrating intensified treatment on those patients who exhibit inadequate molecular responses, clinicians can target the specific population at the greatest risk for progression while sparing molecular responders from unnecessary systemic toxicity. Consequently, integrating cfDNA-based MRD assessment into clinical protocols represents a significant step toward a dynamic management strategy that prioritizes treatment intensification only for those with a demonstrated clinical need.
Beyond the direct quantification of tumor-derived genetic material, the systemic immune landscape offers a critical window into the therapeutic efficacy of EGFR inhibitors. Growing evidence suggests that the interaction between EGFR signaling and the host immune system is a major determinant of clinical success (25). Tyrosine kinase inhibitors such as aumolertinib do not act in isolation; they modulate the tumor microenvironment and induce measurable changes in circulating immune cell populations (26). Monitoring these fluctuations in the peripheral blood-such as the proportions of effector T cells to regulatory T cells or shifts in myeloid-derived suppressor cells-provides a comprehensive view of the treatment response. For instance, a rapid shift toward an immunologically active profile, marked by increased lymphocyte counts or favorable changes in inflammatory indices like the neutrophil-to-lymphocyte ratio (NLR), is frequently associated with prolonged survival. Conversely, a persistent suppressive immune state or an increase in exhaustion markers may indicate that the targeted agent alone is insufficient to achieve durable control. This systemic perspective is particularly valuable in the L858R subgroup, where higher genomic instability often leads to a more complex immune evasion strategy. Integrating immune profiling with cfDNA analysis creates a dual-layered biomarker framework that enhances the detection of minimal residual disease. By identifying patients who fail to mount an effective systemic immune response during the initial treatment phases, clinicians can more accurately select candidates for treatment intensification. Utilizing these peripheral immune signatures as a guide for adding chemotherapy ensures that aggressive intervention is reserved for those whose internal defense mechanisms require additional support to overcome the malignancy. This strategy moves beyond tumor-centric monitoring to incorporate the patient's own biological response, paving the way for a more holistic approach to precision oncology This investigation introduces a novel, phased therapeutic regimen specifically designed to evaluate the utility of early molecular monitoring in EGFR L858R-mutated patients. The treatment sequence begins with aumolertinib monotherapy for two cycles, spanning six weeks, which serves as a critical window to observe the initial sensitivity of the malignancy. Following this induction, all participants transition to a consolidation phase consisting of four cycles of aumolertinib combined with pemetrexed and carboplatin over twelve weeks. The final phase consists of aumolertinib maintenance monotherapy, which continues until the documentation of disease progression. The central aim of this design is to utilize circulating cell-free DNA (cfDNA) as a dynamic indicator of treatment efficacy. By measuring the concentration of mutant EGFR alleles at three distinct time points-baseline (T0), post-lead-in (T1), and post-chemotherapy (T2)-the study intends to quantify the molecular response. This approach addresses the limitations of current static dosing by identifying whether the depth of molecular clearance during the first six weeks can predict long-term clinical outcomes. Patients who show persistent genomic markers at T1, likely harbor the co-mutations or clonal heterogeneity that drives the inferior outcomes typically seen in the L858R subgroup, are hypothesized to be the primary beneficiaries of the subsequent chemotherapy cycles, as these markers often indicate a higher risk of early resistance. This Phase II trial provides the necessary data to establish a molecularly-driven framework for future randomized trials, aiming to distinguish between those who require intensified treatment and those who might maintain stability through targeted therapy alone. By integrating this time-dependent monitoring, the protocol moves toward a response-adapted paradigm that seeks to maximize clinical results while addressing the toxicity concerns associated with universal chemotherapy use. The findings will help define the precise molecular thresholds, such as the required percentage of ctDNA reduction, needed to personalize the management of EGFR-mutant lung cancer in the frontline setting.
Objectives The primary purpose of this study is to evaluate a response-adapted treatment strategy for patients with advanced EGFR L858R-mutated LUAD. While recent evidence from the FLAURA2 trial has established that the combination of third-generation EGFR-TKIs and chemotherapy provides superior progression-free survival and overall survival compared to TKI monotherapy, this "one-size-fits-all" intensification exposes many patients to unnecessary toxicity. Patients harboring the L858R mutation generally experience inferior outcomes compared to those with Ex19del, making them a high-priority group for intensified regimens. However, the degree of benefit from adding chemotherapy varies significantly among individuals. This trial seeks to transition from universal intensification to a precision-based model. By utilizing a six-week "lead-in" period of aumolertinib monotherapy, the study aims to identify patients who achieve an early, profound molecular response versus those with persistent disease. The purpose is to provide a biological rationale for chemotherapy intervention, specifically targeting the subset of patients whose tumors demonstrate inadequate sensitivity to targeted inhibition during the initial phase. Furthermore, this study intends to establish the feasibility of integrating real-time circulating ctDNA to guide subsequent therapeutic decisions. Ultimately, the data generated will provide the foundation for a future Phase III trial designed to spare "molecular responders" from the adverse effects and costs of chemotherapy while maximizing the efficacy of the combination for those in greatest clinical need.
Primary Objective To evaluate the predictive value of early molecular response: To determine the association between the change in EGFR mutant allele fraction in cfDNA after a 6-week aumolertinib lead-in induction phase (T1) and the chemotherapy combination consolidation phase (T2), with the progression-free survival.
Secondary Objectives Clinical Efficacy: To assess the overall objective response rates at T1 and T2 and the median progression-free survival of the entire cohort receiving the phased aumolertinib and chemotherapy regimen.
Safety and Tolerability: To monitor the incidence and severity of adverse events (AEs) according to CTCAE v5.0, specifically focusing on the transition from aumolertinib monotherapy to the combination phase.
Molecular Clearance Rates: To quantify the proportion of patients achieving complete plasma EGFR clearance during the lead-in phase (post-3 weeks [T0.5] and post-6 weeks [T1]) and after the four cycles of combination chemotherapy (T2).
Radiological vs. Molecular Correlation: To compare the depth of response measured by RECIST 1.1 criteria with the quantitative reduction in ctDNA levels at T1 and T2.
Immune Profile Dynamics: To characterize the shifts in circulating immune cell populations (e.g., CD8+ T cells, myeloid-derived suppressor cells) at T0.5, T1 and T2 and their correlation with clinical outcomes.
Co-mutation Analysis: To investigate the impact of baseline co-occurring mutations (e.g., TP53, RB1) on the kinetics of cfDNA reduction and the durability of the response.
Study Design 3.1 Overview This prospective, single-arm, phase II clinical trial adopts a response-adapted, phased treatment framework specifically designed for treatment-naïve patients with advanced lung adenocarcinoma harboring the EGFR L858R mutation. The study departs from the standard concurrent combination model by utilizing a sequential administration strategy to isolate and evaluate early biological signals. The treatment sequence begins with an induction phase, where participants receive aumolertinib monotherapy at 110 mg once daily for six weeks, encompassing two complete cycles. This initial window provides a unique opportunity to monitor the direct impact of aumolertinib on tumor kinetics and the systemic immune environment before the introduction of cytotoxic agents.
Following the induction period, the study transitions into a consolidation phase. In this stage, all patients receive a combination of aumolertinib (110 mg once daily) with intravenous pemetrexed (500 mg/m²) and carboplatin (AUC 5) every three weeks for four cycles, spanning a total of twelve weeks. This intensified phase is intended to eliminate residual clones and address the molecular heterogeneity often associated with the L858R mutation. After finishing the four cycles of chemotherapy, patients enter the maintenance phase, returning to aumolertinib monotherapy. This treatment continues until the documentation of disease progression, the occurrence of unacceptable toxicity, or the withdrawal of consent.
By employing this phased structure, the trial seeks to establish a clear temporal link between early molecular shifts and long-term efficacy. The design intentionally places the liquid biopsy collection points at the end of the lead-in induction phase and the combination consolidation phase to capture the molecular changes achieved by targeted therapy alone and in combination with chemotherapy. This approach aims to validate whether the six-week induction window can serve as a definitive marker for future clinical decisions, allowing for the identification of patients who truly require chemotherapy while potentially sparing low-risk responders from unnecessary side effects in future randomized investigations. The single-arm nature of this phase II trial focuses on the feasibility of this monitoring workflow and the establishment of specific molecular thresholds within a high-risk genomic subgroup.
3.2 Study Schema This is a single arm, phased structure, multicenter, phase II trial. It contains an induction phase (aumolertinib monotherapy), a consolidation phase (combination of aumolertinib and chemotherapy), and a maintenance phase (aumolertinib monotherapy). A schematic diagram of trial design and the schedule of events are as follows.
3.3 Treatment Period Induction Phase Participants will receive aumolertinib monotherapy as study intervention. Aumolertinib will be administered as 110 mg orally once daily for 6 weeks (± 1 week).
Consolidation Phase Participants will receive a combination of aumolertinib and chemotherapy as study intervention. Chemotherapy, consisting of pemetrexed and carboplatin, will be administered as an IV infusion every 3 weeks for 4 cycles. Aumolertinib will be administered as 110 mg orally once daily concurrently during the chemotherapy phase. Pemetrexed will be administered at 500 mg/m2 and carboplatin at AUC of 5, on Day 1 every 3 weeks.
Maintenance Phase Participants will receive aumolertinib monotherapy as study intervention. Aumolertinib will be administered as 110 mg orally once daily continuously until disease progression, occurrence of unacceptable toxicity, or participants' request for withdrawn.
3.4 Stopping Rules or Discontinuation Criteria
The safety and integrity of the trial are maintained through specific criteria for stopping treatment for individual participants or terminating the study as a whole. These rules ensure that no patient is exposed to unnecessary risk and that the scientific objectives remain attainable. A participant will stop receiving the study treatment if any of the following conditions occur:
Disease Progression: Evidence of objective disease progression as defined by the Response Evaluation Criteria in Solid Tumors (RECIST 1.1).
Unacceptable Toxicity: Occurrence of adverse events that, in the opinion of the investigator, cannot be managed by dose reduction or interruption and pose a significant risk to the subject's safety.
Withdrawal of Consent: A patient may choose to stop participating in the study at any time for any reason without penalty.
Protocol Deviation: Any major violation of the protocol that compromises the safety of the patient or the validity of the data.
Investigator Discretion: The principal investigator determines that continuing the treatment is no longer in the best interest of the participant.
Pregnancy: Any female subject who becomes pregnant during the study will immediately stop all trial medications.
Loss to Follow-up: Failure of the subject to return for scheduled visits despite multiple attempts at contact.
Specific phases of the trial may be modified or halted based on interim observations. Lead-in Phase Safety: If more than 25% of patients experience Grade 3 or higher non-hematological toxicities directly related to aumolertinib monotherapy during the initial six-week period, the lead-in duration may be reassessed. Combination Phase Toxicity: If the rate of treatment-related deaths or life-threatening (Grade 4) adverse events during the combination consolidation phase exceeds a predefined safety threshold, the recruitment for this part will be paused for a safety review.
The entire trial will be terminated early if: Safety Signals: The Data Safety Monitoring Board (DSMB) or the Institutional Review Board (IRB) identifies a pattern of severe or unexpected toxicities that outweigh the potential benefits of the phased treatment strategy. Futility: An interim analysis suggests that the probability of achieving the primary objective (significant correlation between early molecular response and PFS) is too low to justify continuing the study. External Evidence: New clinical data from external sources emerge that fundamentally change the standard of care or render the study hypothesis obsolete. Logistical Failures: Significant issues with patient recruitment or the availability of aumolertinib or chemotherapy agents that prevent the study from reaching its statistical power. The management of toxicities will follow established guidelines, including dose interruptions and reductions as practiced in previous aumolertinib investigations. These protocols are designed to maximize patient safety while allowing for the collection of high-quality molecular and clinical data 3.5 Accountability Procedures for the Investigational Products The investigator or a designated study pharmacist is responsible for maintaining precise and complete records regarding the receipt, inventory, dispensing, and return of all investigational products, including aumolertinib, pemetrexed, and carboplatin. All study medications must be stored in a secure, limited-access area under the temperature and environmental conditions specified by the manufacturers to ensure product stability. For the oral component, aumolertinib, participants will receive a specific number of doses for each cycle, and any unused medication along with original containers must be returned to the site at every scheduled visit to facilitate drug reconciliation and compliance monitoring. The administration of intravenous agents, pemetrexed and carboplatin, will be performed by qualified personnel and documented in both the patient's medical records and the study-specific accountability logs, including details of the batch numbers and expiration dates. Final disposition of all unused or returned investigational products, whether through return to the supplier or on-site destruction according to institutional policy, will be documented to provide a comprehensive audit trail for regulatory review. This rigorous tracking process ensures that the investigational products are managed in strict accordance with the protocol and Good Clinical Practice guidelines.
3.6 Data Collection All participant data for this investigation will be captured through protocol-specific case report forms (CRFs), which serve as the primary vehicle for data collection. Site personnel are responsible for entering clinical findings and observations into the CRFs from original source documents, such as medical charts, laboratory reports, and imaging results. Source data are defined as all information in original records and certified copies necessary for the reconstruction and evaluation of the trial. In instances where specific information-such as patient-reported outcomes, certain clinical assessments, or study-specific questionnaires-is documented directly on the CRF without a prior written or electronic record, these entries will be designated as source data. The principal investigator is responsible for maintaining a definitive list of all data points that are recorded directly on the CRFs to ensure transparency during monitoring and auditing. CRFs will be submitted to the Institutional Review Board (IRB) for review and approval before study initiation. Any modifications to the approved CRFs will be submitted to the IRB for review and approval to maintain the integrity of the study and compliance with regulatory standards.
Inclusion Criteria:
Individuals must be at least 18 years of age at the time of signing the informed consent form.
Participants must demonstrate the ability to understand the study procedures and provide written informed consent before any trial-specific activities begin.
A confirmed diagnosis of lung adenocarcinoma (LUAD) via histological or cytological examination is required. The disease must be in an advanced or metastatic stage (stage IIIB, IIIC, or IV by AJCC TNM staging system 9th edition) that is not suitable for curative-intent surgery or radiation therapy.
Documentation of an EGFR L858R mutation is mandatory. This status can be confirmed using tumor tissue or plasma-based molecular testing.
Participants must not have received prior systemic therapy for advanced or metastatic LUAD. Previous adjuvant or neoadjuvant treatments are allowed if they were completed at least 12 months before the first dose of the study medication.
An Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2 is required. The estimated life expectancy of the participant must be at least three months.
Participants must have at least one measurable lesion that has not been previously irradiated, as defined by RECIST 1.1 criteria.
Adequate physiological function must be demonstrated within 14 days before the start of treatment, including:
Bone Marrow: Absolute neutrophil count ≥ 1.5 x 10^9/L, platelet count ≥ 100 x 10^9/L, and hemoglobin ≥ 9.0 g/dL.
Hepatic: Total bilirubin ≤ 1.5 x upper limit of normal (ULN); aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x ULN, or ≤ 5 x ULN if liver metastases are present.
Renal: Serum creatinine ≤ 1.5 x ULN or a calculated creatinine clearance ≥ 45 mL/min.
Reproductive Safety: Participants of childbearing potential must agree to use highly effective contraception throughout the study and for a specified period after the final dose of the investigational products
Exclusion Criteria:
Any previous treatment with EGFR tyrosine kinase inhibitors, including first-, second-, or third-generation agents (e.g., gefitinib, afatinib, or osimertinib).
Patients with symptomatic or unstable central nervous system metastases. However, participants with symptomatic or unstable brain metastases who have completed local treatment and are off high-dose corticosteroids (>10 mg/d prednisone or equivalent) for at least two weeks may be considered eligible.
Severe Comorbidities:
Cardiac: History of clinically significant cardiovascular disease, such as uncontrolled hypertension, congestive heart failure (NYHA Class II or higher), or a recent myocardial infarction within the last six months.
Pulmonary: Known history of interstitial lung disease (ILD) or drug-induced ILD that required steroid treatment.
Gastrointestinal: Malabsorption syndromes or chronic inflammatory bowel disease that could interfere with the absorption of oral aumolertinib.
Concomitant Infections: Active infections requiring systemic therapy. Patients with HBV infection may be eligible if their have received adequate antiviral treatment (antiviral treatment ≥ 7 days before the first dose of the study medication).
Medication Interference: Ongoing use of potent CYP3A4 inhibitors or inducers, as these may significantly alter the plasma concentrations of aumolertinib.
Other Malignancies: A history of another active primary malignancy within the last three years, except for adequately treated non-melanoma skin cancer or in situ carcinoma elsewhere.
Hypersensitivity: Known hypersensitivity to aumolertinib, pemetrexed, carboplatin, or any of the excipients used in these formulations.
216165@h.tmu.edu.tw886-2-27372181
216165@h.tmu.edu.tw886-2-27372181
chaohuachiu@gmail.com
216165@h.tmu.edu.tw886-2-27372181