Research ArticleClinical Studies

Evaluation of Lung Toxicity Related to the Treatment With Alectinib Using a Pharmacovigilance Database

JUNYA SATO, MAYAKO UCHIDA, HARUKA WAKABAYASHI and TADASHI SHIMIZU
Anticancer Research June 2022, 42 (6) 3109-3116; DOI: https://doi.org/10.21873/anticanres.15799

Abstract

Background/Aim: The anaplastic lymphoma kinase (ALK) inhibitor alectinib is recommended as a first-line treatment for ALK lung cancer. Interstitial lung disease is the most common adverse event leading to discontinuation of alectinib. The purpose of this study was to use the Japanese Adverse Drug Event Report database for the evaluation of incidence trends and timing of alectinib toxicity in the lungs. Patients and Methods: Adverse drug reactions (ADRs) by alectinib were extracted between April 2004 and March 2021. Data related to lung toxicity ADRs were analyzed, and the relative risk was estimated using the reporting odds ratio (ROR) and 95% confidence interval (CI). The time of onset of the lung toxicity signs was noted. Results: We obtained 524 reports of ADRs associated with alectinib. Of these, 157 were lung toxicity, including interstitial lung disease, lung disorder, pneumonitis, and pulmonary edema. The RORs for these signs were 10.28 (95%CI=8.38-12.60), 9.19 (5.58-15.13), 7.40 (3.67-14.88), and 7.01 (3.13-15.69), respectively. The median onset times (quartiles, 25-75%) of interstitial lung disease, lung disorder, pneumonitis, and pulmonary edema associated with alectinib treatment were 92 (36-195), 57 (51-129), 228 (62-431), and 83 (22-96) days, respectively. Conclusion: Among the lung toxicity signs, interstitial lung disease had the highest ROR, suggesting a strong causal relationship with alectinib treatment. Interstitial lung disease most frequently developed within 60 days after the start of treatment. These results will be useful for monitoring adverse events associated with the use of alectinib.

Key Words:

Lung cancer with anaplastic lymphoma kinase (ALK) fusion gene (ALK lung cancer) represents about 2-5% of all nonsmall cell lung cancers. ALK lung cancer frequency is particularly high in adenocarcinomas (5-8%) (1). The ALK fusion protein leads to abnormal cell proliferation because of its persistent tyrosine kinase activity. ALK lung cancer is treated with selective ALK inhibitors. Crizonitib was the first ALK inhibitor to be used as a first-line treatment for ALK lung cancer, as it significantly improved progression-free survival [PFS; hazard ratio (HR)=0.45, 95% confidence interval (CI)=0.35-0.60] and overall survival (OS; HR=0.35, 95%CI=0.08-0.72), compared to the effects of the conventional platinum combination chemotherapy (PLOFILE1014) (2). Eventually, ALK inhibitors have become standard drugs for ALK lung cancer treatment. In the original study, crizotinib was continued as a first-line therapy for a median period of 10.9 months, but the developing resistance to this drug was a problem. Therefore, secondary treatments with other ALK inhibitors have been tested. The ALUR study compared the efficacy of alectinib, a second-generation ALK inhibitor, with those of pemetrexed or docetaxel after the emergence of resistance to crizotinib. Treatment with alectinib was associated with longer PFS, which indicated the efficacy of alectinib as a second-line therapy (HR=0.15, 95%CI=0.08-0.29) (3). Subsequently, a head-to-head study (J-ALEX) of crizotinib and alectinib as first-line treatments for ALK inhibitor-naïve patients was conducted in Japan, which showed longer PFS (HR=0.34, 95%CI=0.17-0.71) with alectinib (4). This result was confirmed by an international study (ALEX), which showed similar beneficial results (HR=0.47, 95%CI=0.34-0.65) (5). These studies led to the adoption of alectinib as a standard treatment for ALK lung cancer.

The most frequent adverse events (AEs) associated with alectinib treatment are lung toxicity, constipation, upper respiratory tract infection, hepatic dysfunction, and taste abnormalities. In general, the frequency of drug-induced interstitial lung disease is high in the Japanese population, and it is particularly true in the case of therapy with alectinib. The frequency of interstitial lung disease in the J-ALEX study was relatively high, at 8% (4). Furthermore, interstitial lung disease is the most common cause of alectinib discontinuation because of the life-threatening risk of this condition. Therefore, a detailed analysis of incidence of interstitial lung disease associated with the use of alectinib in Japanese patients is required.

Adverse drug reaction (ADR) data obtained from clinical trials prior to drug approval usually come from relatively small populations of patients with well-defined backgrounds. However, in the real-world clinical practice, the use of approved drugs in a large number of patients with diverse backgrounds may reveal previously unknown ADR profiles. Therefore, pharmacovigilance, which aims to monitor drug safety, is important for the optimal use of all drugs (6-8). Pharmacovigilance is assessed using a spontaneous reporting system (SRS) that reflects the reality of clinical practice (9). In Japan, the Pharmaceuticals and Medical Devices Agency (PMDA) has established the Japan Adverse Drug Event Report (JADER) database as its SRS. In addition, pharmacovigilance allows for the immediate provision of information to healthcare professionals and patients, thereby reducing the risk of ADRs in patients.

The purpose of this study was to analyze retrospectively the JADER database to determine the time profile of interstitial lung disease onset in patients treated with alectinib.

Patients and Methods

We used data from public releases of the JADER database (10-13). This database, available for free download from the PMDA website (14), includes descriptions of ADR cases. We analyzed ADR reports recorded between April 2004 and March 2021. The JADER database consists of four datasets: patient demographic information (DEMO), drug information (DRUG), AEs (REAC), and medical history (HIST). The ADRs in the JADER database were coded according to the terminology preferred by the Medical Dictionary for Regulatory Activities/Japanese version 24.1 (15).

We first removed duplicate cases from the DRUG and REAC tables, as described by Hirooka and Yamada (16). We then used the identification number of each ADR case to merge the corresponding case data from the DRUG, REAC, and DEMO tables. The medication contributions to ADRs were classified as “suspected medicine,” “concomitant medicine,” and “interaction”. We only extracted cases with “suspected medicine” classification.

To investigate the association between treatment with alectinib (ALECENSA® Capsules) and lung toxicity, we examined the association between treatment with alecitinib (ALECENSA® Capsules) and lung toxicity, using JADER database records. Data on lung toxicity from more than five reported cases were extracted, and the relative risk of AEs was estimated using the reporting odds ratio (ROR). ROR is frequently used in the spontaneous reporting database as an indicator of the relative risk of ADR. We constructed 2×2 contingency tables and analyzed the data based on two classifications: the presence or absence of the “pulmonary toxicity” and the presence or absence of suspected alectinib use. We calculated RORs, 95%CIs, and p-values using the Fisher’s exact test. Lung toxicity signs were considered positive when the lower limits of the 95%CIs of the ROR were >1. Furthermore, the detected signs of pulmonary toxicity were compared to those from previous reports. In addition, the detected lung toxicity signs were analyzed for the time of onset, outcome, and treatment. The scale parameter α and shape parameter β were calculated by fitting the Weibull distribution to the time to onset histogram. All statistical analyses were performed using JMP Pro® 16 software (SAS Institute, Cary, NC, USA).

Results

We joined three tables, DRUG (3,875874 reports), REAC (1,096193 reports), and DEMO (693,295 patients), by the ID number and removed duplicate data from the DRUG and REAC tables (16). All data included in the category of “suspected drugs” were extracted and used as the “data table” (1,772494 reports).

We analyzed this data table and found 524 reports of ADRs caused by alectinib. Of these, 157 ADRs were related to lung toxicity (Figure 1). Patient characteristics are shown in Table I. Approximately 61.1% of the patients were women. According to the age distribution of the study population, lung toxicity occurred frequently in patients in their 70s (29.3%).

View this table:
Table I.

Characteristics of the patients exhibiting lung toxicity related to the treatment with alectinib.

Figure 1.
Figure 1.

Process of constructing the data analysis table.

Among the types of lung toxicity caused by alectinib, interstitial lung disease, lung disorder, pneumonitis, pneumonia, and pulmonary edema were reported in 120, 16, 8, 7, and 6 cases, respectively (Table II). The RORs of interstitial lung disease, lung disorder, pneumonitis, pneumonia, and pulmonary edema were 10.28 (95%CI=8.38-12.60, p<0.001), 9.19 (95%CI=5.58-15.13, p<0.001), 7.40 (95%CI=3.67-14.88, p<0.001), 0.49 (95%CI=0.23-1.03, p=0.023), and 7.01 (95%CI=3.13-15.69, p<0.001), respectively. Signals were detected for four (interstitial lung disease, lung disorder, pneumonitis, and pulmonary edema) of the five lung toxicity-related ADRs.

A histogram of the time to onset values showed that the four detected lung toxicity signs occurred 57-228 days after alectinib administration (Figure 2).

Figure 2.
Figure 2.

Histograms of lung toxicity adverse event occurrences for 1) interstitial lung disease, 2) lung disorder, 3) pneumonitis, and 4) pulmonary edema.

The median onset values (quartiles, 25-75%) of interstitial lung disease, lung disorder, pneumonitis, and pulmonary edema caused by alectinib were 92 (36-195), 57 (51-129), 228 (62-431), and 83 (22-96) days, respectively. When fitting the Weibull distribution to the time to onset histogram, the lower limits of the 95%CIs for each lung toxicity shape parameter β were all less than 1 (Table III).

View this table:
Table II.

Numbers of reports and RORs of lung toxicity related to the treatment with alectinib.

View this table:
Table III.

Medians and Weibull parameters of lung toxicity.

The details of the management of the four AEs are shown in Table IV. The most common intervention was discontinuation of treatment, which was recorded in 87.5% of patients with interstitial lung disease, 81.3% of patients with pulmonary edema, and all patients with pneumonitis and pulmonary edema. The percentages of outcomes (recovery, remission, no recovery, death, unknown) are shown in Figure 3. Among the 144 cases for which the four AEs were confirmed to be associated with the use of alectinib, 111 cases (77%) had recovery or remission. However, two patients, one with interstitial lung disease and another with pulmonary edema, had fatal outcomes.

View this table:
Table IV.

Details of management of four types of adverse events associated with the use of alectinib.

Figure 3.
Figure 3.

Outcomes for each adverse event associated with the use of alectinib.

Discussion

In the present study, we used information from the JADER database and analyzed incidence of lung toxicity in 157 patients, following treatment with alectinib. Slightly over 60% of these patients were women, and this sex distribution was similar to the proportion of women in the J-ALEX study (60%) (4). Elderly patients in their 70s were the most common age group in which lung toxicity ADRs were observed. This result was slightly different from the findings of the J-ALEX study, in which the median age of eligible patients was 61 years. Lung toxicity caused by alectinib was divided into the following reported side effects: interstitial lung disease, lung disorder, pneumonitis, pneumonia, and pulmonary edema. Of these, interstitial lung disease had a median onset of 92 days, but the histogram showed that most frequently, this condition occurred within 60 days after the start of the treatment (Figure 2). These quantitative data were similar to those reported in a previous comprehensive survey of the profiles of drug-induced interstitial lung disease in the JADER database (17). In that report, the ROR (95%CI) for lung toxicity associated with alectinib was 10.6 (8.1-13.9), and the median time to onset was 78.5 days. Although the scale parameter β of the Weibull distribution was close to 1, and the parameters did not seem to indicate clearly an initial high incidence of lung toxicity or its increase over time, healthcare professionals should pay a particular attention to symptoms such as dry cough and dyspnea on exertion seen in the first 3 months after the initiation of alectinib treatment, as with high probability, those may be signs of drug-induced lung toxicity. Patients should be provided with this information and be alert. Medical professionals should suspect interstitial lung disease when such respiratory symptoms are observed within these treatment periods, and appropriate examination is necessary. To identify interstitial lung disease, blood tests, chest radiographs, and arterial blood oxygen saturation should be performed immediately. If any of these parameters are abnormal, chest CT and bronchoscopy should be performed. Drug-induced interstitial lung disease has a fatal outcome in 1/3 of cases. This is especially true for the early-onset cases (18). Therefore, early detection and management of interstitial lung disease associated with ALK inhibitor treatment, including steroid administration, are important.

In the present study, the RORs for interstitial lung disease, lung disorder, pneumonitis, and pulmonary edema associated with alectinib administration were remarkably high, ranging from 7 to 10. This suggests that respiratory disorders are particularly important ADRs associated with alectinib treatment. The incidence of interstitial pneumonia in the general patient cohort in Japan is 3.44 per 100,000 (0.003%) (19). On the other hand, the incidence of all interstitial lung diseases in JADER was 2.8%. Thus, the incidence of interstitial pneumonia may be overreported by JADER, because this incidence was calculated in a population in which any AE occurred. The ROR, based on a similar population, does not calculate the incidence of AEs but rather indicates the strength of the causal relationship between the drug use and AE.

In the J-ALEX study in Japanese subjects, interstitial lung disease incidence following therapy with alectinib was 8%, with grade 3-4 pneumonia seen in 5% of cases (4). On the other hand, in the international ALEX study, grade 3-4 pneumonia was never observed (5). In addition, a comprehensive analysis of AEs associated with the use of five ALK inhibitors from the FDA Adverse Event Reporting System reported that the safety profile of ALK inhibitors varies depending on the drug. According to those data, treatment with alectinib was strongly associated with liver function abnormalities, but not with interstitial lung disease (20). Therefore, race/ethnicity may affect the occurrence of interstitial lung disease following treatment with ALK inhibitors. Such ethnicity-specific effects have also been observed in the case of therapy with the first-generation EGFR tyrosine kinase inhibitor gefitinib. The frequency of gefitinib-induced interstitial lung disease in the United States was 0.3% (analysis of 23,000 cases) (21), whereas that in Japan was 5.8% (analysis of 3,322 cases) (22), i.e., ~20 times higher. Risk factors for the development of gefitinib-induced interstitial lung disease include poor performance status, male sex, smoking history, and a previous history of lung disease (23). In the future, we plan to thoroughly analyze the risk factors for lung toxicity associated with alectinib in Japan.

In our study, we also analyzed management of pulmonary toxicity following treatment with alectinib and its outcomes. Although it was not recorded whether direct treatment of lung injury was attempted (e.g., administering steroids), the most common response to the four AEs was discontinuation of treatment. The most common of these outcomes was recovery or minor recovery (77%). In general, most pulmonary toxicities are often fatal. However, the relatively favorable outcome of the AEs associated with the use of alectinib may be explained by the pharmacological properties of this drug, as well as by the fact that alectinib was prescribed by respiratory specialists for the treatment of lung cancer, thus the pulmonary toxicity was detected early and dealt with appropriately.

In addition to alectinib, clinically used ALK inhibitors include crizotinib, ceritinib, lorlatinib, brigutinib, and enzalutinib. Alectinib has never been directly compared to ceritinib or brutinib. The following is a report on drug selection with alectinib, lorlatinib is considered a third-generation ALK inhibitor, which is effective against the fusion protein containing the G1202R mutation associated with the resistance to alectinib (24). Although a small number of patients, the possibility of less efficacy of alectinib in patients who have progressed after ceritinib treatment has been reported (25). Furthermore, it has been reported that OS is no different in elderly ALK lung cancer patients compared to non-elderly patients. ALK inhibitors are also the preferred treatment for elderly patients (26). Based on these, alectinib is considered the standard first-line treatment of ALK lung cancer. Future studies are needed to clarify lung toxicity profiles of all ALK inhibitors used in Japan. Our study did not distinguish whether lung toxicity of alectinib was due to its use as a first-line or a second-line treatment (e.g., after crizotinib or platinum combination chemotherapy). In the PLOFILE1014 study, which compared crizotinib with chemotherapy (platinum plus pemetrexed), lung toxicity was observed in 2% and 1% of the patients, respectively (2). It is unclear whether there is a difference in the lung toxicity profile of alectinib between outcomes of its use as a first-line and second-line therapy.

The J-ALEX study only observed interstitial lung disease in 8 of the 103 patients who received alectinib. In contrast, in the present study, lung toxicity manifestations were noted in 157 patients according to 524 reports of ADRs associated with alectinib. The median follow-up period in the J-ALEX study was only 12.2 months (4). The updated report of the ALEX trial showed that the 5-year OS rate was 62.5%, and during the 48-month OS follow-up period 34.9% of patients were still being treated with alectinib (27).

Long-term observation of AEs associated with the use of alectinib is necessary, and our data included more than 5 years of observation because of the insurance listing of this drug. Our real-world data analysis provided novel, clinically useful information regarding the incidence of interstitial lung disease associated with the use of alectinib, which is important for assessing the safety of this drug in Japan.

There are some limitations in this study, because the JADER database is based on self-reporting. First, unlike it is done in clinical trials and observational studies, we were not able to track all patients treated, therefore the possibility of over-reporting cannot be ruled out. Second, the calculated data on the number of days of incidence does not reflect all reported data, because data without the start date of administration were excluded. Factors that influence pulmonary toxicity include older age, male sex, smoking, low lung function, and low nutrition. However, the JADER did not include patient background factors related to pulmonary toxicity. Therefore, it is unclear whether the patient cohort evaluated in this study differs from the general patient population. Despite these limitations, the results of this study provide important information on the incidence of interstitial lung disease associated with the use of alectinib in Japan.

Conclusion

A comprehensive survey using pharmacovigilance techniques revealed that lung toxicity is more likely to occur within 3 months of alectinib administration. Our findings should make physicians and pharmacists better aware of lung AEs during a long-term treatment with alectinib. These data also provide important information to alert patients using alectinib.

Footnotes

  • Authors’ Contributions

    Mayako Uchida and Tadashi Shimizu provided the idea for this study, defined the methodology, and analyzed the data. Haruka Wakabayashi assisted with data collection under the guidance of Mayako Uchida. Junya Sato, as the first Author, summarized the clinical discussion of the study data and contributed to the preparation and editing of the manuscript.

  • Conflicts of Interest

    The Authors declare no conflicts of interest in relation to this study.

  • Received March 27, 2022.
  • Revision received April 23, 2022.
  • Accepted April 26, 2022.

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Evaluation of Lung Toxicity Related to the Treatment With Alectinib Using a Pharmacovigilance Database
JUNYA SATO, MAYAKO UCHIDA, HARUKA WAKABAYASHI, TADASHI SHIMIZU
Anticancer Research Jun 2022, 42 (6) 3109-3116; DOI: 10.21873/anticanres.15799
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