Abstract
Alectinib is the first‐line therapy for anaplastic lymphoma kinase‐positive non‐small‐cell lung cancer. Although some guidelines have recommended using other anaplastic lymphoma kinase inhibitors after alectinib failure, evidence for such regimens in patients who fail to respond to alectinib is limited. This study involved using administrative claims data from acute care hospitals in Japan. We extracted the data of 634 patients diagnosed with lung cancer between September 1, 2014, and January 31, 2023, who received alectinib treatment before treatment with another anaplastic lymphoma kinase inhibitor. We assessed distributions of patients according to their treatment sequencing and prognosis among three periods defined based on the initial marketing dates of lorlatinib and brigatinib. The type of anaplastic lymphoma kinase inhibitors after alectinib failure changed over time. In the most recent period, lorlatinib (58%) and brigatinib (40%) became predominant. Two‐year overall survival improved over time (47%–84%), accompanied by an increased 2‐year proportion of patients who continuously used anaplastic lymphoma kinase inhibitors after alectinib failure (13%–44%). The times to treatment discontinuation of the regimen between patients treated with lorlatinib and brigatinib were similar, with a hazard ratio of 1.02 (95% confidence interval, 0.64–1.64) in the period after marketing brigatinib. This study provides insights into the evolving treatment landscape for patients with anaplastic lymphoma kinase‐positive non‐small‐cell lung cancer who experience failed alectinib treatment and highlights the need for further studies and data accumulation to determine the optimal treatment strategy.
Keywords: administrative claims database, alectinib, anaplastic lymphoma kinase, brigatinib, lorlatinib
Alectinib is the preferred initial treatment for anaplastic lymphoma kinase (ALK)‐positive non‐small‐cell lung cancer, but when it fails, there is limited evidence for using other ALK inhibitors. This study observed changing trends in post‐alectinib treatment patterns, with lorlatinib and brigatinib becoming more common and 2‐year survival and 2‐year times to treatment discontinuation of the regimen improved over time. Our study provides insights into the evolving treatment landscape for patients with ALK‐positive non‐small‐cell lung cancer who experience failed alectinib treatment.
Abbreviations
- ALK
anaplastic lymphoma kinase
- BMI
body mass index
- CCI
Charlson comorbidity index
- CI
confidence interval
- HR
hazard ratio
- ICD‐10
International Classification of Diseases, 10th Revision
- IPTW
inverse probability of treatment weighting
- MDV
Medical Data Vision Co., Ltd
- NSCLC
non‐small‐cell lung cancer
- OS
overall survival
- PS
propensity score
- SMD
standardized mean difference
- TTD
time to treatment discontinuation
1. INTRODUCTION
Approximately 3%–5% of patients diagnosed with NSCLC have a rearranged ALK gene, which is identified as an oncogenic driver gene. 1 Anaplastic lymphoma kinase inhibitors are currently the standard care for patients with ALK‐positive NSCLC. The first‐generation ALK inhibitor, crizotinib, targets the ATP‐binding site of the ALK protein and yields high response rates and progression‐free survival compared with chemotherapy in the first‐ and second‐line treatments. 2 , 3 However, resistance to crizotinib occurs within 1–2 years. 4 , 5 , 6 , 7 , 8 Several next‐generation ALK inhibitors have become available to improve the prognosis of patients who developed resistance to crizotinib. 9 , 10 , 11 , 12 As of during this study, five ALK inhibitors (crizotinib, alectinib, ceritinib, brigatinib, and lorlatinib) have been approved for clinical use as first‐line treatments for ALK‐positive NSCLC in Japan. Alectinib showed superior efficacy compared with crizotinib in several trials and is recommended and predominantly used as a first‐line therapy for ALK‐positive NSCLC in Japan. 13 , 14 , 15 , 16
New ALK inhibitors are approved every 2–3 years, and some guidelines recommend their subsequent use after the failure of an ALK inhibitor; however, evidence regarding ALK inhibitor treatment after alectinib failure is limited. 17 , 18 , 19 , 20 In this study, we used administrative claims data in Japan to describe the treatment sequencing of ALK inhibitors and patient prognoses over time in patients who failed to respond to alectinib.
2. MATERIALS AND METHODS
2.1. Study design
We undertook a retrospective cohort study using administrative claims data from acute care hospitals in Japan provided by MDV. 21 The data were obtained from discharge summaries and health insurance claims from hospitalizations and outpatient visits at hospitals using the Diagnosis Procedure Combination system. As of May 2023, MDV had a database encompassing data on approximately 43 million patients from over 460 hospitals, representing approximately 26% of acute care hospitals in Japan. 22 In addition, the data contained demographic information, such as patient age, sex, body height, body weight, primary diagnosis, TNM classification, CCI, activities of daily living scale (Barthel index), surgical procedures, chemotherapy drugs administered, radiotherapy, discharge status, medication, and treatment received in the outpatient setting.
Patients were included in this study if they were diagnosed with lung cancer (ICD‐10 code C34) between September 1, 2014 (the initial marketing date of alectinib in Japan) and January 31, 2023. Subsequently, we extracted the data of patients who received alectinib at least once, followed by another ALK inhibitor (crizotinib, ceritinib, lorlatinib, or brigatinib, defined as “alectinib‐sequel ALK inhibitor”) at least once, regardless of whether they had received other non‐ALK inhibitor treatments between the two ALK inhibitor treatments. The study design comprised an index date (date of the first prescription of alectinib‐sequel ALK inhibitors), a baseline period (up to 90 days before the index date, unless otherwise specified), and a follow‐up period (through the last date of any medical procedure available in the database).
This study was carried out in accordance with the Declaration of Helsinki and Good Pharmacoepidemiology Practices. Per the Japanese Ethical Guidelines for Medical and Health Research Involving Human Subjects, ethical review and informed consent were not required, as this was a noninterventional, retrospective study that used anonymized patient data.
2.2. Demographic and clinical information
We analyzed several demographic and clinical characteristics, including age and sex, at the index date, BMI, Barthel index score, and CCI calculated based on medical conditions (determined using ICD‐10 Clinical Modification codes) at the baseline period, histology, smoking history, and diagnoses of brain metastasis (identified using the ICD‐10 code C793) during the last hospital admission before the index date. The definition of demographic and clinical characteristics of the patients are shown in Figure S1.
2.3. Definition of analysis cohort based on calendar period
We divided patients into the following three time periods based on the initial marketing date of lorlatinib and brigatinib: (1) the period after the date of initial marketing of alectinib‐sequel ALK inhibitors and before the initial marketing of lorlatinib (pre‐lorlatinib period: February 2015 to August 2018), (2) after the initial marketing of lorlatinib and before the initial marketing of brigatinib (post‐lorlatinib/pre‐brigatinib period: September 2018 to March 2021), and (3) after the initial marketing of brigatinib (post‐lorlatinib/brigatinib period: April 2021 to January 2023).
2.4. Prognostic measures
Overall survival and the TTD were evaluated as prognostic outcomes. Overall survival was defined as the time from initiating alectinib‐sequel ALK inhibitor treatment to death from any cause. Otherwise, patients' observation was censored on the last date of the follow‐up period. Time to treatment discontinuation was defined as the time from initiating alectinib‐sequel ALK inhibitor treatment to the end of the line due to any of the following events: (1) initiation of the next line, (2) gap of more than 120 days from the last prescription date for alectinib‐sequel ALK inhibitors, or (3) death; otherwise, it was censored at the last date of the follow‐up period. 23 These prognostic measures were obtained within 2 years of the index date.
2.5. Statistical analysis
The frequency and percentage of alectinib‐sequel ALK inhibitor prescriptions were plotted monthly. Patient characteristics and treatment patterns were summarized with calendar periods using the median and interquartile range for continuous variables and frequencies and percentages for categorical variables. For prognostic evaluation, the Kaplan–Meier method was used to evaluate the OS and TTD in each period. All data manipulation and statistical analyses were undertaken using R version 4.2.3 software (R Core Team). 24
2.6. Exploratory analysis
Exploratory post‐hoc analyses for comparing the treatment effects of lorlatinib and brigatinib as alectinib‐sequel ALK inhibitors were carried out. These analyses were limited to patients in the post‐lorlatinib/brigatinib period to minimize the effects of calendar time. The characteristics of lorlatinib and brigatinib users during the post‐lorlatinib/brigatinib period were summarized using the set of descriptive statistics. Considering the follow‐up duration in the post‐lorlatinib/brigatinib period, TTD was compared between lorlatinib and brigatinib.
We used IPTW to adjust for confounding factors and balance the patients' observation. The predicted probabilities of using brigatinib compared with lorlatinib (PS) were computed using a multivariable logistic regression model that considered the following potential confounders: age, sex, BMI, presence of brain metastasis, smoking history, CCI, and the number of lines of alectinib‐sequel ALK inhibitor treatment. To ensure a balance between the lorlatinib and brigatinib groups, we calculated the SMD for each covariate. A threshold for the absolute value of SMD less than 0.1 indicated successful balance. We applied the Kaplan–Meier method to evaluate the TTD. We applied the Kaplan–Meier method to evaluate the TTD using stabilized IPTW. To compare the overall treatment effects, we used stabilized IPTW to estimate the average treatment effect by creating a pseudo‐dataset with PS. 25 We used a weighted Cox proportional hazard regression with robust standard errors to calculate the HR and their 95% CI for TTD. For missing data in the covariates, a multiple imputation method with predictive mean matching was applied. 25 A multiple imputation method with predictive mean matching was applied for missing data in the covariates. 26
2.7. Subgroup analysis
We undertook a subgroup analysis to address discrepancies in the treatment lines after alectinib treatment. First, we strictly identified patients who had received alectinib as a first‐line treatment after being diagnosed with lung cancer. We considered patients who had a minimum interval of 1 month between the date of the first patient's data entry in the database and the date of their initial lung cancer diagnosis to ensure the inclusion of only untreated lung cancer cases evident in the database. Second, we restricted the analysis to patients who received an ALK inhibitor subsequent to alectinib (second‐line subgroup). We defined the group of patients excluded from the second‐line subgroup as the control subgroup. Finally, we undertook the same analysis as described above in the second‐line and control subgroups to verify the differences in the impact on outcomes between the subgroups.
3. RESULTS
3.1. Study cohort
We identified 432,146 patients diagnosed with lung cancer between September 2014 and January 2023. Of these, 2260 received alectinib based on their medical records. We excluded 1626 patients not subsequently treated with ALK inhibitors. In total, 634 patients received alectinib‐sequel ALK inhibitors after alectinib treatment between February 2015 and January 2023 (Figure 1). In the pre‐lorlatinib period (September 2014–October 2018), 127 patients received alectinib‐sequel ALK treatments, of whom 34 (27%) received crizotinib and 93 (73%) received ceritinib as alectinib‐sequel inhibitors. In the post‐lorlatinib/pre‐brigatinib period (November 2018–April 2021), 294 patients received alectinib‐sequel ALK inhibitors, of whom 6 (2%) received crizotinib, 36 (12%) received ceritinib, and 255 (86%) received lorlatinib. In the post‐lorlatinib/brigatinib period (April 2021–January 2023), 206 patients received alectinib‐sequel ALK inhibitors, among which 6 (2.9%) received ceritinib, 121 (58%) received lorlatinib, and 83 (40%) received brigatinib.
FIGURE 1.
Patient flow diagram. ALK, anaplastic lymphoma kinase; ICD‐10, International Classification of Diseases, 10th Revision.
3.2. Description of alectinib‐sequel ALK inhibitor usage using calendar time
Figure 2 shows the changes in the use of alectinib‐sequel ALK inhibitors over time. The use of alectinib‐sequel ALK inhibitors changed with the introduction of new drugs. Although lorlatinib was largely prescribed after approval, it currently shares the largest proportion of prescriptions with brigatinib.
FIGURE 2.
Alectinib‐sequel anaplastic lymphoma kinase (ALK) inhibitor usage in 634 Japanese patients with ALK‐positive non‐small‐cell lung cancer, by calendar time.
3.3. Summary of patient characteristics and treatment patterns
The patient characteristics and treatment patterns across the three periods are summarized in Table 1. A slight increasing trend was observed in the proportion of current or former smokers (from 34% to 39% and 45%), whereas the proportion of patients with adenocarcinoma showed a decreasing trend from 89% to 87% and 80%. Treatment patterns showed a trend toward earlier use of alectinib as first‐line treatment based on the medical records available (from 68% to 76% and 81%) and a trend toward earlier use of crizotinib, lorlatinib, ceritinib, and brigatinib as second‐line treatments (from 46% to 61% and 70%). We also included details of treatments following alectinib‐sequel ALK inhibitor derived from the database. The treatments post‐alectinib‐sequel were similar across each period.
TABLE 1.
Summary of patient characteristics and treatment patterns in 634 Japanese patients with anaplastic lymphoma kinase (ALK)‐positive non‐small‐cell lung cancer.
| Characteristic | Overall N = 634 | Pre‐lorlatinib period, n = 127 | Post‐lorlatinib/pre‐brigatinib period, n = 297 | Post‐lorlatinib/brigatinib period, n = 210 |
|---|---|---|---|---|
| Age, years | 62 (51, 72) | 63 (53, 70) | 63 (53, 72) | 60 (49, 72) |
| Sex | ||||
| Female | 351 (55) | 77 (61) | 170 (57) | 104 (50) |
| Male | 283 (45) | 50 (39) | 127 (43) | 106 (50) |
| BMI | 22.4 (20.1, 25.1) | 21.2 (18.8, 24.0) | 22.5 (20.4, 25.5) | 22.9 (20.5, 25.4) |
| Missing, n | 174 | 24 | 77 | 73 |
| Barthel index | 100 (100, 100) | 100 (100, 100) | 100 (100, 100) | 100 (100, 100) |
| Missing, n | 191 | 25 | 86 | 80 |
| Brain metastasis | ||||
| Yes | 216 (34) | 42 (33) | 102 (34) | 72 (34) |
| No | 418 (66) | 85 (67) | 195 (66) | 138 (66) |
| Smoking history | ||||
| Current/past | 207 (40) | 34 (34) | 95 (39) | 78 (45) |
| Never | 309 (60) | 66 (66) | 149 (61) | 94 (55) |
| Missing | 118 | 27 | 53 | 38 |
| Histology | ||||
| Adenocarcinoma | 537 (85) | 113 (89) | 257 (87) | 167 (80) |
| Squamous | 2 (0.3) | 0 (0) | 1 (0.3) | 1 (0.5) |
| Other | 95 (15) | 14 (11) | 39 (13) | 42 (20) |
| CCI | ||||
| 0–2 | 415 (65) | 79 (62) | 196 (66) | 140 (67) |
| ≥3 | 219 (35) | 48 (38) | 101 (34) | 70 (33) |
| Alectinib treatment lines | ||||
| 1 | 482 (76) | 86 (68) | 226 (76) | 170 (81) |
| ≥2 | 152 (24) | 41 (32) | 71 (24) | 40 (19) |
| Alectinib‐sequel ALKi treatment lines | ||||
| 2 | 386 (61) | 58 (46) | 181 (61) | 147 (70) |
| ≥3 | 248 (39) | 69 (54) | 116 (39) | 63 (30) |
| Lines of therapy before alectinib‐sequel ALKi after alectinib | ||||
| 0 | 520 (82) | 93 (73) | 243 (82) | 184 (88) |
| ≥1 | 114 (18) | 34 (27) | 54 (18) | 26 (12) |
| After alectinib‐sequel treatment a | ||||
| Non‐ALKi treatment | 175 (51) | 44 (52) | 90 (51) | 41 (48) |
| Platinum based | 118 (34) | 25 (30) | 59 (34) | 34 (40) |
| Taxane based | 169 (49) | 40 (48) | 85 (49) | 44 (52) |
| Pemetrexed based | 11 (3.2) | 4 (4.8) | 5 (2.9) | 2 (2.4) |
| ALKi treatment | 169 (49) | 40 (48) | 85 (49) | 44 (52) |
Note: Data are shown as median (IQR) or n (%), unless otherwise indicated.
Abbreviations: ALKi, ALK inhibitor; BMI, body mass index; CCI, Charlson comorbidity index.
Total number of patients who received the subsequent treatment after alectinib‐sequel treatment was 344, in pre‐lorlatinib period was 84, in post‐lorlatinib/pre‐brigatinib period was 175, in post‐lorlatinib/brigatinib period was 85.
3.4. Description of prognostic measures
The findings for estimated OS and TTD are presented in Figure 3A,B, respectively. The 1‐year OS values were 47% (95% CI, 38%–58%), 75% (95% CI, 70%–80%), and 84% (95% CI, 77%–91%) in the pre‐lorlatinib, post‐lorlatinib/pre‐brigatinib, and post‐lorlatinib/brigatinib periods, respectively. The corresponding 1‐year TTD values were 13% (95% CI, 7.8%–21%), 43% (95% CI, 37%–49%), and 44% (95% CI, 36%–54%), respectively. The median TTD for each period was 70 days (95% CI, 44–98 days), 259 days (95% CI, 195–350 days), and 294 days (95% CI, 210–413 days), respectively.
FIGURE 3.
Overall survival and time to treatment discontinuation in 634 Japanese patients with anaplastic lymphoma kinase‐positive non‐small‐cell lung cancer. (A) Overall survival and (B) time to treatment discontinuation in the entire study population. (C) Overall survival and (D) time to treatment discontinuation in the second‐line subgroup. (E) Overall survival and (F) time to treatment discontinuation in the control subgroup.
In the subgroup analysis, we identified 120 patients in the second‐line subgroup and 514 in the control subgroup. The OS and TTD of each subgroup were similar in this population (Figure 3C–F). As a post‐hoc analysis, we assessed OS by further subgrouping based on posttreatment with alectinib‐sequel, categorizing it as a non‐ALK inhibitor or ALK inhibitor. No clear difference in OS was observed among non‐ALK inhibitor or ALK inhibitor groups (Figure S2).
3.5. Comparison of lorlatinib and brigatinib usage in the post‐lorlatinib/brigatinib period
The patient characteristics in both treatment groups are summarized in Table 2. No clinically significant differences were observed between the lorlatinib and brigatinib users. Considering the follow‐up duration in the post‐lorlatinib/brigatinib period, TTD was compared between lorlatinib and brigatinib users with statistical adjustment for observed potential confounders using the stabilized IPTW method. The results are shown in Figure 4. In the stabilized IPTW analysis, the patient characteristics were well balanced (Figure S3A). No differences were observed in the estimated TTD between lorlatinib and brigatinib users within 1 year (HR, 1.02; 95% CI, 0.64–1.64; p = 0.919).
TABLE 2.
Characteristics of patients treated with lorlatinib or brigatinib among patients with anaplastic lymphoma kinase (ALK)‐positive non‐small‐cell lung cancer who failed to respond to alectinib.
| Characteristic | Lorlatinib, n = 121 | Brigatinib, n = 83 |
|---|---|---|
| Age, years | 62 (50, 72) | 59 (45, 72) |
| Sex | ||
| Female | 56 (46) | 45 (54) |
| Male | 65 (54) | 38 (46) |
| BMI | 22.8 (20.4, 24.9) | 23.0 (20.5, 26.0) |
| Missing, n | 44 | 25 |
| Barthel index | 100 (100, 100) | 100 (100, 100) |
| Missing, n | 48 | 26 |
| Brain metastasis | ||
| Yes | 40 (33) | 30 (36) |
| No | 81 (67) | 53 (64) |
| Smoking history | ||
| Current/past | 46 (46) | 29 (43) |
| Never | 53 (54) | 38 (57) |
| Missing, n | 22 | 16 |
| Histology | ||
| Adenocarcinoma | 96 (79) | 65 (78) |
| Squamous | 0 (0) | 1 (1.2) |
| Other | 25 (21) | 17 (20) |
| CCI | ||
| 0–2 | 88 (73) | 50 (60) |
| ≥3 | 33 (27) | 33 (40) |
| Alectinib treatment lines | ||
| 1 | 99 (82) | 66 (80) |
| ≥2 | 22 (18) | 17 (20) |
| Alectinib‐sequel ALKi treatment lines | ||
| 2 | 82 (68) | 61 (73) |
| ≥3 | 39 (32) | 22 (27) |
| Lines of therapy before alectinib‐sequel ALKi after alectinib | ||
| 0 | 102 (84) | 77 (93) |
| ≥1 | 19 (16) | 6 (7.2) |
Note: Data are shown as median (IQR) or n (%), unless otherwise indicated.
Abbreviations: ALKi, ALK inhibitor; BMI, body mass index; CCI, Charlson comorbidity index.
FIGURE 4.
Comparison of treatment efficacy between lorlatinib and brigatinib in 634 Japanese patients with anaplastic lymphoma kinase (ALK)‐positive non‐small‐cell lung cancer in the post‐lorlatinib/brigatinib period. Kaplan–Meier curves of time to treatment discontinuation for lorlatinib versus brigatinib using inverse probability treatment weighting (IPTW) in the (A) entire study cohort, (B) second‐line subgroup, and (C) control subgroup. The IPTW‐adjusted hazard ratio (HR) of time to treatment discontinuation for patients treated with brigatinib in comparison with those treated with lorlatinib. CI, confidence interval.
In the subgroup analysis, we identified 54 and 150 patients in the second‐line and control subgroups, respectively. In the second‐line subgroup, 32 and 22 patients received lorlatinib and brigatinib, respectively. Patient characteristics in these subgroups were well balanced after using the IPTW method (Figure S3B,C). The HR of TTD in the second‐line subgroup was 1.07 (95% CI, 0.36–3.17; p = 0.900) and that in the control subgroup was 0.90 (95% CI, 0.52–1.59; p = 0.723; Figure 4B,C).
4. DISCUSSION
We explored the ALK inhibitor treatment patterns and patient outcomes after alectinib failure. This study revealed that alectinib‐sequel ALK inhibitors have changed excessively over time and that lorlatinib and brigatinib are currently the major options. Similarly, our findings indicated a trend toward earlier use of alectinib‐sequel ALK inhibitors. The OS and TTD among alectinib‐sequel ALK inhibitor users improved over time. No established treatment strategies currently exist for patients with ALK‐positive NSCLC who fail to respond to alectinib treatment. As the patient cohort was small, the question of the most appropriate alectinib‐sequel therapy could be addressed by analyzing real‐world data from observational studies. In our study, calendar time strongly correlated with alectinib‐sequel ALK inhibitor treatment patterns, suggesting the need to control for its influence in these studies. Therefore, we compared lorlatinib and brigatinib in the post‐lorlatinib/brigatinib period and found that patients receiving both drugs had comparable TTD within 1 year. A more comprehensive evaluation with appropriate controls for intercalendar year effects is expected in the future.
The changing use of novel agents with time has improved outcomes in patients with NSCLC. A retrospective study carried out between 1995 and 2017 reported that introducing new drug classes and a paradigm shift in the treatment of advanced NSCLC improved patient survival. 27 However, that study did not address the prognostic impact of introducing several new ALK inhibitors, as its observation period only extended up to 2017. Our study showed that patients tended to receive newer ALK inhibitors after alectinib failure, and their prognosis improved over time. The improvement of prognosis observed in our study could be attributable to treatments administered before or after alectinib‐sequel ALK inhibitors. To specifically evaluate the influence of treatments received between alectinib and alectinib‐sequel treatments, we undertook a subgroup analysis dividing the second‐line subgroup and the control subgroup. The results of this analysis were consistent with those observed in the entire cohort. We also assessed OS by further subgrouping based on posttreatment with alectinib‐sequel, categorizing it as non‐ALK inhibitor or ALK inhibitor. Similar to the above subgroup analysis, there was no apparent difference in OS between patients treated with ALK inhibitors and those receiving non‐ALK inhibitor therapies post‐alectinib‐sequel ALK inhibitor treatment. These results suggest that the observed improvement in prognosis might not be strongly linked to treatments administered either before or after the use of alectinib‐sequel ALK inhibitors.
First, our findings showed a significant change in the drug usage patterns for treating ALK‐positive NSCLC when comparing the pre‐lorlatinib and post‐lorlatinib/pre‐brigatinib periods. Over these periods, lorlatinib became the most used drug (86%), while the usage of the first‐generation crizotinib declined significantly from 27% to 2% and that of ceritinib decreased from 73% to 12%. The decline in crizotinib usage could be attributed to the superiority of other ALK inhibitors in clinical trials, 2 , 28 while the reduced usage of ceritinib after alectinib failure can be attributed to the side‐effect warnings in Japan and inadequate clear outcomes. 29 Lorlatinib showed efficacy in brain metastasis and mutations, and its approval by the FDA in 2018 for treating patients with alectinib‐refractory ALK‐positive NSCLC based on the results of a phase II study may have made it a promising option. 30 , 31 , 32 A significant change between the pre‐lorlatinib and post‐lorlatinib/pre‐brigatinib periods was the marked improvement in OS and time to disease progression, likely associated with increased lorlatinib use.
In comparing the post‐lorlatinib/pre‐brigatinib and post‐lorlatinib/brigatinib periods, the introduction of brigatinib prompted changes in drug use. Our findings showed that ceritinib was rarely used (12%–2.9%), lorlatinib usage decreased (86%–58%), and brigatinib was newly used (40%). Lorlatinib reportedly causes central nervous system side‐effects; thus, unlike other ALK inhibitors, brigatinib might have been chosen for safety reasons. 33 Another reason for selecting brigatinib may have been due to its effectiveness in patients with brain metastases. 28 Changes in OS and TTD were less pronounced between the post‐lorlatinib/pre‐brigatinib and post‐lorlatinib/brigatinib periods than those between the pre‐lorlatinib and post‐lorlatinib/pre‐brigatinib periods. The less pronounced changes in OS and TTD were convincing because of the insignificant differences in the TTD between the lorlatinib and brigatinib treatments (HR, 1.02; 95% CI, 0.64–1.64; p = 0.919). These results suggest that lorlatinib and brigatinib could be optimal options after alectinib treatment.
This study has some limitations. First, the database did not contain information on several characteristics, such as ECOG PS, metastasis details, ALK status, or induced resistance mechanisms. In addition, the database did not provide information regarding oral compliance, reasons for treatment discontinuation (e.g., progression, toxicity, or resistance), or relapse patterns. The lack of data for these clinical characteristics in the database could have limited our assessments of efficacy due to confounding bias. Second, the database only provided information on admissions to the same hospital; therefore, information before admission to a hospital and after discharge was unavailable. Similarly, censored cases were defined based on information from the last date of any medical procedure. A longer follow‐up period is required for further interpretation. Third, the assessment of the impact post‐alectinib‐sequel treatment was limited due to the small number of patients. This limitation could affect the observed OS following the failure of alectinib‐sequel treatment, as patient demographics and treatment responses may vary over the course of the study. While no clear difference was observed upon further subgrouping by posttreatment (ALK inhibitors vs. non‐ALK inhibitors) with alectinib‐sequel, more definitive evaluations are warranted.
Finally, the observation period (until January 2023) for this real‐world study might be insufficient to assess the OS in patients treated with alectinib‐sequel ALK inhibitors during the post‐lorlatinib/brigatinib period (from April 2021 to January 2023). The shorter observation period cause the insufficient number of events to assess OS. Therefore, we refrained from undertaking a comparison of OS between lorlatinib and brigatinib in the post‐lorlatinib/brigatinib period to avoid misleading information. Future research endeavors could benefit from longer observation periods, using more comprehensive data sources, and incorporating additional clinical parameters to enhance the robustness of the conclusions drawn in this real‐world study.
In conclusion, this study identified the evolving role of ALK inhibitors in patients with ALK‐positive NSCLC who failed to respond to alectinib treatment. The usage of alectinib‐sequel ALK inhibitors as well as the treatment lines have changed significantly over time. Based on these findings, we compared the efficacy of drugs from the same period without comparing drugs from different periods and found that the two drugs used recently differed insignificantly in TTD. More data are required to clarify the appropriate approach for alectinib‐sequel ALK inhibitor treatment.
AUTHOR CONTRIBUTIONS
Yuki Shimomura: Conceptualization; data curation; formal analysis; investigation; methodology; software; validation; visualization; writing – original draft. Kenji Sawa: Conceptualization; data curation; writing – original draft; writing – review and editing. Takumi Imai: Conceptualization; methodology; supervision; writing – original draft; writing – review and editing. Yasutaka Ihara: Data curation; formal analysis; software; validation; writing – review and editing. Hisako Yoshida: Supervision; writing – review and editing. Ayumi Shintani: Conceptualization; funding acquisition; methodology; project administration; resources; supervision; writing – review and editing.
FUNDING INFORMATION
None.
CONFLICT OF INTEREST STATEMENT
KS received lecture fees from Eli Lilly Japan, AstraZeneca, Ono Pharmaceutical, Nippon Kayaku, Chugai Pharmaceutical, Taiho Pharmaceutical, Nippon Boehringer Ingelheim, and Kyowa Kirin. TI received lecture fees from JCR Pharmaceuticals and Kyowa Kirin. AS received lecture fees from AbbVie, AstraZeneca plc, Asahi Kasei Corporation, Astellas Pharma, Bayer Yakuhin, Bristol Myers Squibb, Chugai Pharmaceutical, Daiichi Sankyo, Eisai, Janssen Pharmaceutical, Kissei Pharmaceutical, Kyowa Kirin, Mallinckrodt Pharmaceuticals, Maruho, Merck Biopharma, Mitsubishi Tanabe Pharma Corporation, Nipro Corporation, Nippon Shinyaku, Novo Nordisk Pharma, Ono Pharmaceutical, Pfizer, Shionogi Pharma, Taisho Pharmaceutical, Takeda Pharmaceutical Company Limited, and Torii Pharmaceutical. The other authors have no conflict of interest.
ETHICS STATEMENT
Approval of the research protocol by an institutional review board: This study was carried out in accordance with the Declaration of Helsinki and Good Pharmacoepidemiology Practices. Per the Japanese Ethical Guidelines for Medical and Health Research Involving Human Subjects, ethical review and informed consent were not required, as this was a noninterventional, retrospective study that used anonymized patient data.
Informed consent: N/A.
Registry and the registration no. of the study/trial: N/A.
Animal studies: N/A.
Supporting information
Figure S1.
ACKNOWLEDGMENTS
We want to thank all staff and their families. We also thank Editage for English language editing.
Shimomura Y, Sawa K, Imai T, Ihara Y, Yoshida H, Shintani A. Treatment sequencing after failure to alectinib in patients with anaplastic lymphoma kinase‐positive non‐small‐cell lung cancer. Cancer Sci. 2024;115:926‐936. doi: 10.1111/cas.16056
DATA AVAILABILITY STATEMENT
The claims database used for this study can only be obtained by purchasing from a vendor (Medical Data Vision Co., Ltd; http://www.mdv.co.jp/).
REFERENCES
- 1. Solomon B, Varella‐Garcia M, Camidge DR. ALK gene rearrangements: a new therapeutic target in a molecularly defined subset of non‐small cell lung cancer. J Thorac Oncol. 2009;4(12):1450‐1454. doi: 10.1097/JTO.0b013e3181c4dedb [DOI] [PubMed] [Google Scholar]
- 2. Shaw AT, Bauer TM, de Marinis F, et al. First‐line lorlatinib or crizotinib in advanced ALK‐positive lung cancer. N Engl J Med. 2020;383(21):2018‐2029. doi: 10.1056/NEJMoa2027187 [DOI] [PubMed] [Google Scholar]
- 3. Shaw AT, Kim DW, Nakagawa K, et al. Crizotinib versus chemotherapy in advanced ALK‐positive lung cancer. N Engl J Med. 2013;368(25):2385‐2394. doi: 10.1056/NEJMoa1214886 [DOI] [PubMed] [Google Scholar]
- 4. Gainor JF, Dardaei L, Yoda S, et al. Molecular mechanisms of resistance to first‐ and second‐generation ALK inhibitors in ALK‐rearranged lung cancer. Cancer Discov. 2016;6(10):1118‐1133. doi: 10.1158/2159-8290.CD-16-0596 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5. Katayama R, Shaw AT, Khan TM, et al. Mechanisms of acquired crizotinib resistance in ALK‐rearranged lung cancers. Sci Transl Med. 2012;4(120):120ra17. doi: 10.1126/scitranslmed.3003316 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6. Yamaguchi N, Lucena‐Araujo AR, Nakayama S, et al. Dual ALK and EGFR inhibition targets a mechanism of acquired resistance to the tyrosine kinase inhibitor crizotinib in ALK rearranged lung cancer. Lung Cancer. 2014;83(1):37‐43. doi: 10.1016/j.lungcan.2013.09.019 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7. Costa DB, Shaw AT, Ou SH, et al. Clinical experience with crizotinib in patients with advanced ALK‐rearranged non‐small‐cell lung cancer and brain metastases. J Clin Oncol. 2015;33(17):1881‐1888. doi: 10.1200/JCO.2014.59.0539 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8. Guérin A, Sasane M, Zhang J, et al. Brain metastases in patients with ALK+ non‐small cell lung cancer: clinical symptoms, treatment patterns and economic burden. J Med Econ. 2015;18(4):312‐322. doi: 10.3111/13696998.2014.1003644 [DOI] [PubMed] [Google Scholar]
- 9. Wolf J, Helland Å, Oh IJ, et al. Final efficacy and safety data, and exploratory molecular profiling from the phase III ALUR study of alectinib versus chemotherapy in crizotinib‐pretreated ALK‐positive non‐small‐cell lung cancer. ESMO Open. 2022;7(1):100333. doi: 10.1016/j.esmoop.2021.100333 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10. Shaw AT, Kim TM, Crinò L, et al. Ceritinib versus chemotherapy in patients with ALK‐rearranged non‐small‐cell lung cancer previously given chemotherapy and crizotinib (ASCEND‐5): a randomised, controlled, open‐label, phase 3 trial. Lancet Oncol. 2017;18(7):874‐886. doi: 10.1016/S1470-2045(17)30339-X [DOI] [PubMed] [Google Scholar]
- 11. Solomon BJ, Besse B, Bauer TM, et al. Lorlatinib in patients with ALK‐positive non‐small‐cell lung cancer: results from a global phase 2 study. Lancet Oncol. 2018;19(12):1654‐1667. doi: 10.1016/S1470-2045(18)30649-1 [DOI] [PubMed] [Google Scholar]
- 12. Kim DW, Tiseo M, Ahn MJ, et al. Brigatinib in patients with crizotinib‐refractory anaplastic lymphoma kinase‐positive non‐small‐cell lung cancer: a randomized, multicenter phase II trial. J Clin Oncol. 2017;35(22):2490‐2498. doi: 10.1200/JCO.2016.71.5904 [DOI] [PubMed] [Google Scholar]
- 13. The Japanese Lung Cancer Society . Lung cancer clinical practice guidelines. 2022. Accessed July 11, 2023. https://www.haigan.gr.jp/guideline/2022/
- 14. Zhou C, Kim SW, Reungwetwattana T, et al. Alectinib versus crizotinib in untreated Asian patients with anaplastic lymphoma kinase‐positive non‐small‐cell lung cancer (ALESIA): a randomised phase 3 study. Lancet Respir Med. 2019;7(5):437‐446. doi: 10.1016/S2213-2600(19)30053-0 [DOI] [PubMed] [Google Scholar]
- 15. Hida T, Nokihara H, Kondo M, et al. Alectinib versus crizotinib in patients with ALK‐positive non‐small‐cell lung cancer (J‐ALEX): an open‐label, randomised phase 3 trial. Lancet. 2017;390(10089):29‐39. doi: 10.1016/S0140-6736(17)30565-2 [DOI] [PubMed] [Google Scholar]
- 16. Peters S, Camidge DR, Shaw AT, et al. Alectinib versus crizotinib in untreated ALK‐positive non‐small‐cell lung cancer. N Engl J Med. 2017;377(9):829‐838. doi: 10.1056/NEJMoa1704795 [DOI] [PubMed] [Google Scholar]
- 17. Nishio M, Yoshida T, Kumagai T, et al. Brigatinib in Japanese patients with ALK‐positive NSCLC previously treated with alectinib and other tyrosine kinase inhibitors: outcomes of the phase 2 J‐ALTA trial. J Thorac Oncol. 2021;16(3):452‐463. doi: 10.1016/j.jtho.2020.11.004 [DOI] [PubMed] [Google Scholar]
- 18. Seto T, Hayashi H, Satouchi M, et al. Lorlatinib in previously treated anaplastic lymphoma kinase‐rearranged non‐small cell lung cancer: Japanese subgroup analysis of a global study. Cancer Sci. 2020;111(10):3726‐3738. doi: 10.1111/cas.14576 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19. Sugawara S, Kondo M, Yokoyama T, et al. Brigatinib in Japanese patients with tyrosine kinase inhibitor‐naive ALK‐positive non‐small cell lung cancer: first results from the phase 2 J‐ALTA study. Int J Clin Oncol. 2022;27(12):1828‐1838. doi: 10.1007/s10147-022-02232-7 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20. Goto Y, Shukuya T, Murata A, et al. Real‐world therapeutic effectiveness of lorlatinib after alectinib in Japanese patients with ALK‐positive non‐small‐cell lung cancer. Cancer Sci. 2023;114(6):2560‐2568. doi: 10.1111/cas.15777 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21. Yasunaga H. Real world data in Japan: chapter II the diagnosis procedure combination database. Ann Clin Epidemiol. 2019;1(3):76‐79. doi: 10.37737/ace.1.3_76 [DOI] [Google Scholar]
- 22. Medical Data Vision . About MDV Database. Accessed July 11, 2023. http://www.mdv.co.jp/
- 23. Jahanzeb M, Lin HM, Pan X, et al. Real‐world treatment patterns and progression‐free survival associated with anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor therapies for ALK+ non‐small cell lung cancer. Oncologist. 2020;25(10):867‐877. doi: 10.1634/theoncologist.2020-0011 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24. R Core Team . R: A Language and Environment for Statistical Computing. R Foundation for Statistical Computing; 2021. Accessed July 11, 2023. https://www.R‐project.org/ [Google Scholar]
- 25. Austin PC, Stuart EA. Moving towards best practice when using inverse probability of treatment weighting (IPTW) using the propensity score to estimate causal treatment effects in observational studies. Stat Med. 2015;34(28):3661‐3679. doi: 10.1002/sim.6607 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26. Buuren SV, Groothuis‐Oudshoorn K. Mice: multivariate imputation by chained equations. R J Stat Soft. 2011;45(3):1‐67. doi: 10.18637/jss.v045.i03 [DOI] [Google Scholar]
- 27. Takano N, Ariyasu R, Koyama J, et al. Improvement in the survival of patients with stage IV non‐small‐cell lung cancer: experience in a single institutional 1995‐2017. Lung Cancer. 2019;131:69‐77. doi: 10.1016/j.lungcan.2019.03.008 [DOI] [PubMed] [Google Scholar]
- 28. Camidge DR, Kim HR, Ahn MJ, et al. Brigatinib versus crizotinib in advanced ALK inhibitor‐naive ALK‐positive non‐small cell lung cancer: second interim analysis of the phase III ALTA‐1L trial. J Clin Oncol. 2020;38(31):3592‐3603. doi: 10.1200/JCO.20.00505 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 29. Pharmaceuticals and Medical Devices Agency . Notification of Safety Measures (Pharmaceuticals). Accessed July 11, 2023. https://www.pmda.go.jp/files/000237612.pdf
- 30. Lorbrena . Highlights of prescribing information. Accessed July 11, 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210868s000lbl.pdf
- 31. Johnson TW, Richardson PF, Bailey S, et al. Discovery of (10R)‐7‐amino‐12‐fluoro‐2,10,16‐trimethyl‐15‐oxo‐10,15,16,17‐tetrahydro‐2H‐8,4‐(metheno)pyrazolo[4,3‐h][2,5,11]‐benzoxadiazacyclotetradecine‐3‐carbonitrile (PF‐06463922), a macrocyclic inhibitor of anaplastic lymphoma kinase (ALK) and c‐ROS oncogene 1 (ROS1) with preclinical brain exposure and broad‐spectrum potency against ALK‐resistant mutations. J Med Chem. 2014;57(11):4720‐4744. doi: 10.1021/jm500261q [DOI] [PubMed] [Google Scholar]
- 32. Bauer TM, Shaw AT, Johnson ML, et al. Brain penetration of lorlatinib: cumulative incidences of CNS and non‐CNS progression with lorlatinib in patients with previously treated ALK‐positive non‐small‐cell lung cancer. Target Oncol. 2020;15(1):55‐65. doi: 10.1007/s11523-020-00702-4 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 33. Bauer TM, Felip E, Solomon BJ, et al. Clinical management of adverse events associated with lorlatinib. Oncologist. 2019;24(8):1103‐1110. doi: 10.1634/theoncologist.2018-0380 [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Figure S1.
Data Availability Statement
The claims database used for this study can only be obtained by purchasing from a vendor (Medical Data Vision Co., Ltd; http://www.mdv.co.jp/).