Efficacy and safety of 40 mg osimertinib administered every other day for non‐small cell lung cancer harboring an epidermal growth factor receptor mutation: A single‐center retrospective cohort study

Abstract Osimertinib is a first‐line or adjuvant therapy for non‐small cell lung cancer (NSCLC) harboring an epidermal growth factor receptor (EGFR) mutation. However, owing to the adverse events associated with treatment, certain patients cannot maintain a daily regimen of 80 or 40 mg. In this study, we examined the efficacy of 40 mg of osimertinib administered every other day. In this single‐center, retrospective study, we evaluated patients with NSCLC harboring an EGFR mutation in whom treatment was initiated with 40 mg osimertinib every other day at our institution between May 2016 and June 2023. The major outcome was the duration of administering 40 mg osimertinib every other day. Six patients with NSCLC were evaluated. The median duration of 40 mg osimertinib intake every other day was 12.6 months. Four of the six patients weighed below 50 kg, and four experienced weight loss. Additionally, four of the six patients had severe renal impairment upon receiving 40 mg osimertinib every other day. Thus, our findings suggest the efficacy of administering 40 mg osimertinib every other day in patients with low bodyweight, weight loss, or severe renal impairment.


INTRODUCTION
Epidermal growth factor receptor (EGFR) mutations are the most common mutations in non-small cell lung cancer (NSCLC).Osimertinib is effective against EGFR mutation, especially the EGFR T790M mutation, 1 and is recommended as the first-line therapy for EGFR-mutated NSCLC 2 and also recommended as adjuvant therapy for completely resected stage II-IIIA EGFR-mutated NSCLC. 3 According to the FLAURA and ADAURA trials, 2,3 15% and 10% of patients, respectively, cannot maintain continuous osimertinib use owing to its adverse effects.Thus, extending the duration of effective osimertinib treatment is essential to maintain activities of daily living (ADL) and prolong survival.
Cytotoxic agents can cause severe adverse events such as nausea and decreased appetite, which are associated with decreased ADL.In phase III trials, the incidence of any grade of nausea and decreased appetite attributable to cytotoxic agents was 33.8%-43.3%and 19.0%-26.0%,][6] Thus, some patients refuse treatment with cytotoxic agents because of their toxicities.The efficacy of gefitinib, a firstgeneration EGFR tyrosine kinase inhibitor, administered every other day, has been demonstrated. 7,8However, the efficacy of 40 mg of osimertinib administered every other day has not yet been reported.

Study population
In this single-center, retrospective, cohort study, we included patients who received 40 or 80 mg osimertinib for NSCLC harboring an EGFR mutation between May 2016 and June 2023 at the Kameda Medical Center.The exclusion criteria included patients not receiving 40 mg osimertinib every other day, those receiving osimertinib as adjuvant therapy, and those lacking exon 19 deletion or exon 21 L858R point mutation.The Cobas EGFR mutation test was used to detect EGFR mutations, while PD-L1 expression was assessed using the PD-L1 IHC 22C3 pharmDx assay.The study protocol complied with the Declaration of Helsinki and was approved by the Institutional Review Board of Kameda Medical Center "23-032."The requirement for written informed consent was waived owing to the study's retrospective nature, with no interventions performed on the patients.

Treatment strategy
All patients received initial osimertinib doses of 80 mg.Doses were tapered to 40 mg once daily, followed by 40 mg every other day when patients could not be reliably administered a specific dose owing to adverse events.The attending physician decided the initial dose of osimertinib and reduced it according to adverse events experienced.

Data collection
Data regarding patient age, sex, performance status, height, bodyweight, body mass index, pathology of lung cancer, TNM stage (according to the staging criteria of the American Joint Committee on Cancer, eighth edition), EGFR mutation status, total proportion of score of PD-L1 (TPS), treatment line, blood test (to detect white blood cell and platelet counts and aspartate aminotransferase, alkaline phosphatase, creatine phosphatase, albumin, and creatinine levels), duration of osimertinib use at any dose, best response to initial treatment, and details of each adverse event were extracted from medical records.TPS was classified into three groups (high, ≥50%; low, 1-49%: negative, <1%).
The major outcome was the duration of administering 40 mg osimertinib every other day.The total duration of osimertinib administration at any dose, the progression-free survival (PFS) for patients receiving 40 mg of osimertinib every other day, and relative dose intensity (RDI) of the whole duration of administering osimertinib were assessed.PFS was defined as the time from the initiation of osimertinib to disease progression or death from any cause.Efficacy was assessed from the computed tomography results according to the Response Evaluation Criteria in Solid Tumors version 1.1.Adverse events were graded using the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0.Categorical variables are shown as percentages (%), and continuous variables as medians (25-75 percentiles).The Kaplan-Meier method was used to estimate the dose duration and PFS for patients taking 40 mg osimertinib every other day and the overall duration of osimertinib administration at any dose using EZR on R commander version 1.61.This was a retrospective case study with a limited number of patients; thus, we did not use hypothetical testing.

RESULTS
Of the 151 patients receiving osimertinib at varying doses and treatment lines for NSCLC harboring EGFR mutations, six patients met the inclusion criteria (Figure 1).The median age was 79 years, and five were female.All patients' performance statuses were 0 or 1.All histological findings confirmed adenocarcinomas, and five of the six cases harbored the L858R mutation.Four of the six patients had severe renal impairment (Table 1).The median duration of 40 mg osimertinib administered every other day and median PFS were both 12.6 months (3.0-NA), the median overall duration of osimertinib treatment was 30.7 months (17.5-NA), and the median RDI was 45.1%.As of June 30, 2023, two patients received 40 mg osimertinib every other day (Table 2).Four patients ceased osimertinib treatment because of tumor progression.Four patients maintained their performance status, whereas two patients with worsened performance opted not to receive second-line therapy.Of the six, four patients' bodyweights were below 50 kg, and four patients lost weight compared with that before taking the initial dose of osimertinib and at the start of 40 mg osimertinib administration every other day.Furthermore, five patients experienced renal impairment, and two patients' renal impairment worsened before taking 40 mg osimertinib every other day.In one patient, grade 3 platelet count decreased and creatine phosphokinase levels increased.Two patients experienced appetite loss and an acneiform rash (Table 3).

DISCUSSION
According to the AURA trial, 9 the objective response rate associated with 20 mg osimertinib once daily was 52%.These data showed that 40 mg osimertinib administered every other day could benefit some patients.The mean (min-max) area under the concentration-time curve from 0 to time τ over the dosing interval at steady state (AUCτ) for 20 mg and 40 mg of osimertinib was 1965 (873-4990) and 5636 (2040-14 100) nMh, respectively, and the mean (min-max) Cmax values were 106.3 (45.4-280) nM and 305.1 (128-807) nM, respectively.This finding suggests that the AUCτ and Cmax for a dose of 20 mg is expected to be comparable to those for a dose of 40 mg for some patients.In this study, the plasma concentration of 40 mg osimertinib administered every other day might be similar to that of 40 mg osimertinib administered once daily in regular patients because the change in their bodyweight and renal function might influence the pharmacokinetic (PK) model of osimertinib.Osimertinib dose reduction has been reported as a risk to brain metastasis control. 10Consequently, it is necessary to carefully consider the risks associated with osimertinib dose reduction.No patient had brain metastasis after taking osimertinib 40 mg every other day in this study.
Bodyweight has the largest effect on the PK model. 11Moreover, toxicity occurs more frequently in patients with moderate renal impairment and low bodyweight, 12 and osimertinib's PK may be related to ethnicity and food. 13Here, three of the six patients lost over 5 kg bodyweight, and four of the six patients' bodyweights were under 50 kg when they started osimertinib administration every other day.Inability of such patients to tolerate osimertinib may be attributed to their low bodyweight. 11,12After the dose de-escalation of osimertinib, the patients continued osimertinib treatment.Patients with severe renal impairments reportedly have 1.85-and 1.62-fold higher exposure to osimertinib and its metabolites, respectively, than patients with normal renal function. 14Four out of six patients had severe renal impairment when they started receiving osimertinib every other day.Here, plasma osimertinib concentrations might have been high in some patients owing to renal impairment.
According to the FLAURA study, 2 interstitial lung disease, pneumonitis, and QT prolongation are the most common events leading to permanent discontinuation in the osimertinib arm.Plasma osimertinib concentration can affect the probability of rash and diarrhea. 12In this study, patients experienced rash, diarrhea, appetite loss, and QT prolongation.However, these adverse events resolved after dose de-escalation of osimertinib and patients could continue osimertinib treatment.Therefore, we should be careful of the osimertinib dose in a patient with low bodyweight or severe renal failure. 11ur study had some limitations.It was retrospective in nature, and there were variations in decision-making regarding osimertinib dose changes.Additionally, a limited number of participants were included in this study, and blood osimertinib concentrations were not determined.
In conclusion, our findings suggest the efficacy of administering 40 mg osimertinib every other day in patients with EGFR-mutant NSCLC exhibiting low bodyweight, weight loss, or severe renal impairment, particularly when standard-dose osimertinib is not well-tolerated.

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I G U R E 1 Patient disposition in this study.NSCLC, non-small cell lung cancer.
Patient characteristics.Results of this study.Characteristics of the six patients.