The study was designed and conducted as an observational, phase IV PMS study of axitinib (product name: Inlyta) with a planned study period of 9 years. Eligible patients were required to be adult (aged > 18 years) patients with histologically-confirmed advanced RCC, failed to a prior first-line systemic therapy with tyrosine kinase inhibitors, and to have a measurable metastatic lesion(s). As this was an all-case PMS study, patients either who were already taking axitinib or who started taking axitinib during the study period were all invited to the study if the eligibility criteria were met. After obtaining a signed written informed consent, the patient was followed up until consent withdrawal, death, or the end of the study period, whichever came first. As per study protocol, safety follow-up data were collected from the day of first axitinib dose to up to at least 28 days after the last dose. Study-related data were collected from medical records and laboratory test results. As the study was designed as a multicenter, observational study under routine clinical practices, all clinical decisions, including the dosing and treatment duration of axitinib, were up to local clinical practice standards and the investigator’s clinical judgment.

As per prescription guidelines, it was recommended that second-line axitinib at a starting dose of 5 mg twice daily was administrated orally without interruption. Supportive care including the administration of blood products, and the use of analgesics was given if judged appropriately by the treating physicians. Treatment schedule, evaluations, and follow-up were judged at the discretion of treating oncologists. Axitinib was continued until disease progression, unacceptable toxicity, or consent withdrawal. Dose adjustments at the start of a new cycle were based on the worst toxicity observed during the previous cycle, in accordance with the AXIS trial protocol [5].

Patient’s demographic data, laboratory test results, axitinib administration details, concomitant medications, and tumor assessment results were collected during routine clinical practice. In addition, any observed or reported adverse events, regardless of the relationship with axitinib, were collected since the first dose of axitinib. The severity of an adverse event was graded according to the Common Terminology Criteria for Adverse Events ver. 5.0. Except for those of which causality was evaluated to be unlikely, all adverse events were attributed to axitinib. Tumor lesions were measured unidimensional according to the Response Evaluation Criteria in Solid Tumors ver. 1.1. The objective response rate (ORR) was defined as the proportion of patients achieving the best overall response of complete response or partial response. Progression-free survival (PFS) was defined as the time from the first dose of axitinib to the first documentation of objective tumor progression or death due to any cause, whichever occurred first. All study data were captured on the electronic case report form and monitored by the designated study monitors.

As the study was an observational study, the sample size was estimated based on the available target patients. At least 100 patients were to be enrolled and followed up for 9 years. Patients who received at least one dose of axitinib and had safety data were included in the analysis. Continuous variables were summarized with descriptive statistics, and categorical variables were presented with frequency and percentage. Adverse events were coded with the Medical Dictionary for Regulatory Activities (MedDRA) ver. 24.0. Although no formal comparisons between groups were planned, if needed, proportions between subgroups were compared using chi-square or Fisher exact test. Logistic regression analysis was performed to identify a factor affecting the ORR. A two-sided p-value less than 0.05 was considered to be statistically significant. Survival time was calculated using the Kaplan-Meier method. All statistical analyses were carried out with SAS ver. 9.4 (SAS Institute Inc., Cary, NC).

Among a total of 125 patients with advanced RCC enrolled between August 2012 and August 2021 21 hospitals in Korea, 111 patients were considered eligible for the present analyses. Reasons for exclusion included: (1) starting dose was different from the approved product label (n=10), (2) axitinib was given as third-line treatment (n=2), (3) patient refusal (n=1), and (4) no evidence of disease progression after first-line therapy (n=1). The majority (81%) of patients were male; age ranged from 30 to 84 years with a median of 65 years (Table 1). Except in one patient with histologically co-existing papillary type 2 and clear cell RCC, all were diagnosed with clear cell RCC. And as first-line of systemic therapy, the number of patients with sunitinib was 51 (46%), pazopanib was 57 (51%) and other treatment was 3 (3%), respectively. The median duration between the start of first-line systemic tyrosine kinase inhibitors and the time of axitinib treatment initiation was 28 months, and in 27% of patients, the duration was 60 months or longer. The most commonly involved metastatic site was lung (77%) and next was bone (28%). About 70% of patients previously received surgical resection of the primary tumor. The numbers of patients receiving prior immunotherapy or radiation therapy were one (0.90%) and 26 (23%), respectively.

Except in one patient, a treatment period of axitinib was available. The duration of axitinib administration ranged from 15 days to 25 months with a median of 5.6 months. About 48% of patients received axitinib for 6 months or longer. The median daily dose of axitinib was 10 mg (range, 4.36 to 15.95 mg). Axitinib daily dose was maintained at 10 mg in 65% of patients. Dose escalation of axitinib above 10 mg daily was possible in six patients (5%).

Ninety-two patients (83%) experienced 338 adverse events, 71% (264/338) of which were evaluated to be related to axitinib. Serious adverse events were reported in 14 patients (12%), and most adverse events were generally well tolerated and easily manageable. Most commonly reported adverse event was diarrhea (36%), followed by hypertension, stomatitis, decreased appetite, palmar-plantar erythrodysesthesia, and asthenia (Table 2). Axitinib dose was reduced in 20%, and axitinib was discontinued in 8% of the patients. Twenty-three unexpected adverse drug reactions were experienced by 16 patients (14%) (S1 Table), and none of them was reported as a serious adverse drug reaction. No statistical difference in the incidence of adverse events was found in the subgroups based on age or hospitalization status (Table 3). However, women had higher adverse event incidence than men (100% vs. 79%, p=0.021).

The proportion of severe (grade 3 or higher) adverse events was 12% (39/338) (Table 2). During the study period, two deaths were reported. One patient, a 75-year-old woman was found dead at home after 18 months of axitinib therapy. This event was thought unlikely to be related to study treatment because her disease remained stable and no serious adverse events were reported until then. Another patient, a 57-year-old man with multiple bone and brain metastases experienced disease progression and died 1 month after starting second-line axitinib. This event was considered to be not related to axitinib but to underlying disease.

With a median follow-up duration of 8 months, the median PFS was 12.4 months (95% confidence interval [CI], 9.6 to 18.9) (Table 4, Fig. 1). The ORR was 30%, with 4% of complete response and 26% of partial response. No statistical difference in the ORR was found between the subgroups by demographics, baseline characteristics, concomitant medications, or axitinib doses (Table 5, S2 Table). However, patients with a shorter duration of axitinib administration had a worse ORR than the other two subgroups (10% [< 90 days] vs. 41% [90 to 179 days] or 36% [≥ 180 days], p=0.018). Multiple logistic regression analysis also showed that longer administration of axitinib was associated with a greater ORR with the odds ratio of 1.11 (95% CI, 1.02 to 1.20) (p=0.011). Of the total 111 patients, there were six patients who increased the dose at least one time. The overall treatment duration and ORR of all patients and patients with dose escalation were shown in Fig. 2, and the overall treatment duration and response were favorable despite of the dose escalation. In particular, among six patients who had at least one axitinib dose escalation event, two of them had relatively long-term duration of axitinib treatments, which were initiated following pazopanib as first-line therapy in both patients. One patient, a 66-year-old male, received axitinib with mean daily dose of 15.1 mg for 20.6 months and maintained stable disease while on axitinib treatment. The other patient, a 67-year-old male, received axitinib with mean daily dose of 16.4 mg for 14.9 months and had partial response till disease progress. Adverse events reported in both patients included dysphonia, diarrhea, and pruritus, which were all mild in intensity.