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

Abstract

Background

Little is known about real‐world treatment and outcomes of patients with anaplastic lymphoma kinase‐positive (ALK+) advanced non‐small cell lung cancer (NSCLC).

Patients and Methods

This retrospective study of the Flatiron Health EHR‐derived deidentified database included patients with a lung cancer diagnosis and confirmed advanced NSCLC who received ALK tyrosine kinase inhibitor (TKI) therapy (January 1, 2011, through June 30, 2018). Patient characteristics and treatment patterns were characterized. Real‐world progression‐free survival (rwPFS) and time to discontinuation were calculated using the Kaplan‐Meier method.

Results

First‐line ALK TKI therapy was administered to 581 patients (27.5% had brain metastasis on or prior to initiation) and second‐line ALK TKI therapy to 254 patients post crizotinib (45.7% had brain metastasis on or prior to second‐line ALK TKI initiation). Crizotinib (84.6%; n = 492) was the most commonly administered first‐line ALK TKI therapy. For second‐line ALK TKI post crizotinib (n = 254), 49.6% received ceritinib, 41.7% received alectinib, 5.9% received crizotinib retreatment, and 2.8% received brigatinib. Median (95% confidence interval [CI]) rwPFS was 7.47 (6.48–8.32) months for first‐line and 7.30 (5.72–8.42) months for second‐line ALK TKI. Median (95% CI) rwPFS was significantly longer among first‐line ALK TKI patients without than with brain metastasis (8.52 [7.57–10.59] vs. 4.97 [3.75–5.99] months; p < .0001) and patients with brain metastasis on or prior to first‐line ALK TKI therapy had a significantly increased risk of progression (hazard ratio ± SE, 1.976 ± 0.112; p < .0001).

Conclusion

Median rwPFS in patients with advanced ALK+ NSCLC was < 8 months for first‐ and second‐line ALK TKI therapy and was even shorter in patients with brain metastasis, highlighting the need for more effective treatments in this patient population.

Implications for Practice

Results presented herein describe real‐world treatment of advanced ALK+ NSCLC with ALK TKI therapies from January 2011 through June 2018. Crizotinib was the most commonly prescribed first‐line ALK TKI therapy in this patient population, but the majority of data analyzed were obtained prior to Food and Drug Administration approval of alectinib and ceritinib in the first‐line ALK TKI setting. Physicians should monitor patients closely to help identify when a change in treatment should occur.

Introduction

Non‐small cell lung cancer (NSCLC) comprises multiple pathologies with unique molecular signatures [1]. Anaplastic lymphoma kinase (ALK) gene rearrangement is present in a subset (3%–13%) of patients with NSCLC; generally these patients are younger, nonsmokers, and have adenocarcinoma [2]. Patients with NSCLC characterized by ALK rearrangements may benefit from ALK tyrosine kinase inhibitor (TKI) therapies [2].

Crizotinib was the first ALK TKI approved for patients with ALK‐rearranged (i.e., ALK‐positive [ALK+]) NSCLC and has improved efficacy relative to conventional chemotherapy as both first‐line and second‐line therapy in patients with advanced disease [3, 4]. As systemic treatment for patients with advanced ALK‐rearranged NSCLC, median progression‐free survival (PFS) with crizotinib in the first‐line ALK TKI setting ranged from 6.9 to 11.1 months in the PROFILE 1005, 1007, 1014, and 1029 clinical trials [3–6]. However, patients typically acquire resistance to crizotinib through various mechanisms within the first year of treatment [7, 8]. Additionally, crizotinib has poor activity against brain metastasis due to poor penetration of the blood‐brain barrier [9–11]. Results of a retrospective analysis of PROFILE 1005 and 1007 clinical trial data showed that an additional 20% of patients without brain metastasis at crizotinib initiation developed brain metastasis on therapy, and 70% of the patients with known brain metastasis at baseline developed new brain lesions or progression while receiving crizotinib [12].

U.S. Food and Drug Administration (FDA)–approved next‐generation ALK TKIs include ceritinib [13] and alectinib [14] for first‐line treatment of patients with ALK+ metastatic NSCLC and brigatinib [15] for the treatment of patients with ALK+ disease progressing on or intolerant to crizotinib. In the crizotinib‐refractory setting, median PFS reported in clinical trials varied from 6.9 to 7.2 months for ceritinib, 8.2 to 8.9 months for alectinib, and 16.7 months for brigatinib [16]. Most recently, lorlatinib has been approved for use in the U.S. for patients whose disease has progressed on crizotinib and one additional ALK TKI therapy or after failure of alectinib or ceritinib [17].

Although ALK TKIs have improved overall response rates in clinical trials relative to conventional chemotherapy [3, 4, 18, 19], the prognosis for patients with ALK+ NSCLC remains poor. Little is known about the real‐world treatment of patients with advanced ALK+ NSCLC, and results from real‐world studies are needed to better understand treatment patterns and potential unmet needs with current therapies in clinical practice. Results from analyses that evaluate clinical endpoints that can be obtained from real‐world data, such as real‐world progression‐free survival (rwPFS) or its surrogate endpoint of time to treatment discontinuation (TTD), provide information on real‐world usage, supplement data obtained from efficacy trials, and can help provide a more complete picture of treatment in this patient population.

To better understand the unmet needs of current therapies, we conducted a real‐world database analysis and summarized the characteristics of patients with ALK+ advanced NSCLC treated with ALK TKI therapy, described treatment pathways and duration for these patients, and examined rwPFS and TTD for patients receiving first‐line and second‐line ALK TKI therapy overall and for the subgroups of patients with and without pre‐existing brain metastasis at ALK TKI initiation.

Subjects, Materials, and Methods

Data Source

We conducted this retrospective study using the Flatiron Health database: a demographically and geographically diverse longitudinal deidentified database derived from data obtained from electronic health records (EHRs) in the U.S. [20, 21]. The database includes information from more than 265 cancer clinics (approximately 800 sites of care), representing more than 2 million U.S. patients with cancer available for analysis. Data provided to third parties are deidentified and provisions are in place to prevent reidentification, thereby protecting patient confidentiality. Patient‐level data include structured data (i.e., data organized in a predefined manner, such as drop‐down fields that reside in an EHR to capture a patient's sex or date of birth) and unstructured data (i.e., information that is not organized in a pre‐existing data model, such as free text from a physician note or laboratory report) curated via technology‐enabled abstraction. Data from January 1, 2011, through June 30, 2018, were included.

Study Population

Data included are those for patients with an International Classification of Diseases (ICD) diagnosis of lung cancer (ICD‐9 162.x or ICD‐10 C34.x, C39.9) and confirmed diagnosis of advanced NSCLC, including patients with stage IIIB or IV NSCLC at diagnosis or those who presented with earlier stage NSCLC but subsequently developed advanced disease. Data were included if the patient had two or more clinic encounters occurring on or after January 1, 2011; had documentation of ALK rearrangement or translocation (i.e., ALK+), as identified by unstructured data; and received at least one ALK TKI therapy (i.e., crizotinib, ceritinib, alectinib, or brigatinib) following advanced NSCLC diagnosis, regardless of line of therapy, as confirmed by unstructured data. Patients were excluded if they had a gap of more than 90 days between diagnosis of advanced NSCLC and initiation of structured data.

Outcomes Evaluated and Measured

Patient demographic and clinical characteristics were identified from the EHR data. First and second lines of ALK TKI treatment were identified. Patients not previously treated with an ALK TKI comprised the first‐line ALK TKI therapy group. In patients receiving a second line of ALK TKI therapy, the second‐line ALK TKI could be the same as the first‐line ALK TKI if the patient restarted after a gap of more than 120 days.

We defined rwPFS as a distinct episode in which the treating clinician concluded that there had been growth or worsening of the disease of interest, in contrast to the RECIST version 1.1 criteria used to define PFS in the clinical trials for the therapies of interest [3, 6]. The rwPFS data were abstracted and reviewed by trained medical reviewers from unstructured data using clinician's notes, chart documentation, and source evidence (e.g., radiology report, pathologic evidence) [22, 23]. Real‐world PFS for first‐ and second‐line ALK TKI therapy was estimated as the time from treatment start to the earliest of progression or death; otherwise, it was censored at the last follow‐up. Additionally, rwPFS was evaluated by type of ALK TKI therapy received and by the presence or absence of brain metastasis prior to initiation of ALK TKI therapy.

Time to treatment discontinuation and overall survival (OS) were also evaluated. Time to treatment discontinuation was defined as time from initiation of current ALK TKI line to the end of the current line if there were any of the following: (a) initiation of next‐line ALK TKI, (b) gap of more than 120 days between current ALK TKI therapy and last follow‐up date, or (c) death; otherwise, it was censored at the last follow‐up. Overall survival was defined as the time from initiation of current ALK TKI treatment line to death from any cause; otherwise, it was censored at the last follow‐up.

Statistical Analysis

Baseline patient demographic and clinical characteristics were summarized using standard descriptive statistics: continuous variables were reported as mean and SD, and categorical variables were reported as frequency and percentage. The Kaplan‐Meier method was used to evaluate rwPFS and TTD for first‐line ALK TKI therapy and second‐line ALK TKI post crizotinib, as well as by agent and for patients with and without prior brain metastasis; the resulting Kaplan‐Meier curves were then compared. The Kaplan‐Meier method was also used to evaluate and compare OS for first‐line ALK TKI therapy and second‐line ALK TKI post crizotinib, as well as for patients with and without prior brain metastasis.

Multivariate Cox proportional hazard models were used to evaluate predictors of rwPFS and TTD. The models were adjusted for the following covariates: age, sex, race, region, disease stage, practice type, year of ALK TKI therapy initiation, smoking status, presence or absence of prior brain metastasis, and first‐line and second‐line ALK TKI therapy received.

Results

Patient Selection

In total, 581 patients with advanced ALK+ NSCLC received at least one line of ALK TKI therapy and were included in the analysis (Fig. 1). Among the 169 ALK+ patients who were excluded from the analysis, the majority received either platinum‐based chemotherapy combinations or programmed death‐1 (PD‐1)/programmed death‐ligand 1 (PD‐L1)–based therapies. The mean age of included patients at initiation of first‐line ALK TKI therapy was 60.9 years and most patients had stage IV disease at diagnosis (Table 1). Brain metastasis was present in 27.5% of patients on or prior to initiation of first‐line ALK TKI and 45.7% of patients on or prior to initiation of second‐line ALK TKI post crizotinib.

Treatment Pathways

Approximately 85% of patients (n = 492) received crizotinib as first‐line ALK TKI therapy; the rest received alectinib (n = 80; 13.7%) or ceritinib (n = 9; 1.5%). Of the 492 patients who received crizotinib as first‐line ALK TKI, 254 were treated with second‐line ALK TKI therapy. The most commonly administered second‐line ALK TKI therapy post crizotinib was ceritinib (n = 126 patients; 49.6%), followed by alectinib (n = 106; 41.7%), crizotinib retreatment (n = 15; 5.9%), and brigatinib (n = 7; 2.8%).

Treatment Discontinuation

The median (95% confidence interval [CI]) TTD was 7.04 (6.48–8.32) months for first‐line ALK TKI therapy and 9.61 (7.93–11.68) months for second‐line ALK TKI therapy (Fig. 2). Of the 581 patients receiving first‐line ALK TKI therapy, discontinuation was observed for 453 patients (78.0%), whereas 128 (22.0%) remained on treatment at end of follow‐up. Of the 254 patients receiving second‐line ALK TKI therapy, discontinuation was observed for 164 patients (64.6%), whereas 90 (35.4%) remained on treatment at end of follow‐up.

Treatment Discontinuation Risk

Factors identified as significantly increasing the risk of treatment discontinuation for patients receiving first‐line ALK TKI therapy were initiating ALK TKI therapy in the years 2016 (vs. 2011; hazard ratio ± SE, 2.027 ± 0.350; p = .0434) or 2017 (vs. 2011; hazard ratio ± SE, 2.332 ± 0.365; p = .0203) and prior brain metastasis (yes vs. no; hazard ratio ± SE, 1.980 ± 0.113; p < .0001; supplemental online Table 1). Patients who received alectinib versus crizotinib as first‐line ALK TKI therapy had significantly lower treatment discontinuation risk (hazard ratio ± SE, 0.144 ± 0.339; p < .001). For patients receiving second‐line ALK TKI therapy, stage III disease at diagnosis (vs. stage I; hazard ratio ± SE, 4.486 ± 0.762; p = .0487) was identified as significantly increasing treatment discontinuation risk.

Real‐world Progression‐Free Survival

Overall, median rwPFS for first‐line ALK TKI therapy was 7.47 months (Fig. 3). Stratified by first‐line ALK TKI therapy received, median (95% CI) rwPFS for crizotinib (n = 492) was 6.64 (5.99–7.80) months, median rwPFS for alectinib (n = 80) was not reached (9.77 months to not reached), and for ceritinib (n = 9) was 11.05 (0.76–26.05) months.

In patients receiving a second line of ALK TKI therapy post crizotinib (n = 254), overall median (95% CI) rwPFS was 7.30 (5.72–8.42) months (Fig. 4). Median (95% CI) rwPFS was 9.24 (6.28–13.16) months for alectinib as second‐line ALK TKI (n = 106), 11.32 (8.49–11.45) months for brigatinib (n = 7), 5.43 (4.18–8.09) months for ceritinib (n = 126), and 4.64 (2.04–6.18) months for retreatment with crizotinib (n = 15).

Real‐world PFS Stratified by History of Brain Metastasis On or Prior to the Initiation of ALK TKI Therapy

Median (95% CI) rwPFS was significantly longer among patients without brain metastasis on or prior to the initiation of first‐line ALK TKI therapy (8.52 [7.57–10.59] months) compared with those with brain metastasis (4.97 [3.75–5.99] months; p < .0001; Fig. 5A). No significant difference in median rwPFS was found between patients with and without brain metastasis on or prior to second‐line ALK TKI therapy post crizotinib (p = .1932; Fig. 5B).

Progression Risk

Two factors were identified as significantly increasing the risk of progression for patients receiving first‐line ALK TKI therapy: history of smoking (hazard ratio ± SE, 1.295 ± 0.102; p = .0113) and prior brain metastasis (yes vs. no; hazard ratio ± SE, 1.976 ± 0.112; p < .0001; Table 2). Patients who received alectinib versus crizotinib as first‐line ALK TKI therapy had significantly lower progression risk (hazard ratio ± SE, 0.257 ± 0.309; p < .001). For patients receiving second‐line ALK TKI therapy, stage III disease at diagnosis (vs. stage I; hazard ratio ± SE, 5.100 ± 0.632; p = .0100), stage IV disease at diagnosis (vs. stage I; hazard ratio ± SE, 3.900 ± 0.604; p = .0241), and history of smoking (hazard ratio ± SE, 1.383 ± 0.163; p = .0465) were identified as increasing progression risk, whereas second‐line treatment with alectinib (vs. crizotinib; hazard ratio ± SE, 0.493 ± 0.319; p = .0269) was identified as lowering progression risk.

Overall Survival

Among all evaluable patients, median OS for first‐line ALK TKI therapy was 25.79 months (95% CI, 21.15–31.41 months). Median (95% CI) OS was significantly longer among patients without brain metastasis on or prior to initiation of first‐line ALK TKI therapy (31.41 [24.93–37.83] months) compared with those with brain metastasis (15.46 [10.69–21.15] months; p = .0002; supplemental online Fig. 1). In patients receiving a second line of ALK TKI therapy post crizotinib, median (95% CI) OS was 24.64 (15.92–39.05) months. No significant difference in median OS was found between patients with and without brain metastasis on or prior to second‐line ALK TKI therapy post crizotinib (24.84 months [16.88 months to not reached] vs. 19.24 months [13.52 months to not reached]; p = .74; supplemental online Fig. 1).

Discussion

This retrospective database analysis provides insights into real‐world treatment patterns, outcomes, and unmet needs among U.S. patients with advanced ALK+ NSCLC undergoing treatment with crizotinib, ceritinib, and alectinib as first‐ or second‐line ALK TKI therapy, and brigatinib as second‐line ALK TKI therapy. From January 2011 through June 2018, crizotinib was the most commonly prescribed first‐line ALK TKI therapy (84.6% of patients). Overall, patients exhibited a median rwPFS of 7.47 months with first‐line ALK TKI therapy and 7.30 months for second‐line ALK TKI therapy. The median TTD was 7.04 months for first‐line ALK TKI therapy and 9.61 months for second‐line ALK TKI therapy. Compared with patients without brain metastasis on or prior to initiation of first‐line ALK TKI therapy, median rwPFS was significantly shorter for patients with brain metastasis (4.97 vs. 8.52 months, p < .0001), and these patients had a significantly higher risk of progression on first‐line ALK TKI therapy (hazard ratio, 1.976; p < .0001).

The rwPFS for crizotinib as first line of ALK TKI therapy in our analysis (6.64 months) is similar to the results of previous real‐world analyses (6.1 to 9.5 months) [24–27] but is shorter than the PFS reported for crizotinib in the PROFILE 1007 (7.7 months), J‐ALEX (10.2 months), PROFILE 1014 (10.9 months), PROFILE 1029 (11.1 months), and ALEX (11.1 months) clinical trials [3, 4, 6, 28, 29]. However, clinical and radiologic tumor assessment of rwPFS is allowed during a wide range of timepoints (e.g., every 8–16 weeks) and patient population is less rigorously selected, so we expected variation between the results of our analysis and results from clinical trials. For example, our population was older on average compared with the clinical trials and included patients previously treated with chemotherapy or concurrently receiving chemotherapy with ALK TKI therapy. The difference may also be driven by the definition of PFS used in the clinical trials (i.e., RECIST version 1.1 criteria [3, 6]) compared with our definition of rwPFS (i.e., growth or worsening of the disease as decided by the treating physician). However, concordance between real‐world outcomes (e.g., rwPFS) and RECIST‐based outcomes (e.g., PFS) has been noted in letrozole‐treated patients with metastatic breast cancer [30].

Median (95% CI) OS for first‐line ALK TKI therapy in our real‐world analysis (25.79 [21.15–31.41] months) differed from the OS observed with crizotinib in the PROFILE 1014 trial (not reached [45.8 months to not reached]; median follow‐up of approximately 46 months) [31]. Our lower OS results may be influenced by the inclusion of study data from as early as the year 2011 and the limited availability of next‐generation ALK TKI therapies for subsequent therapy, particularly for patients who were treated within the community setting.

In the second‐line ALK TKI setting, median rwPFS post crizotinib in our analysis was 7.30 months overall (n = 254). Median rwPFS with ceritinib as second ALK TKI therapy was 5.43 months (n = 126) in our analysis, which is in line with the PFS reported in the ASCEND‐5 (5.4 months [n = 115]), ASCEND‐2 (5.7 months [n = 140]), and ASCEND‐1 (6.9 months [n = 163]) clinical trials, respectively [19, 32, 33]. Similarly, our rwPFS result of 9.24 months (n = 106) for second‐line alectinib is in line with the PFS reported for alectinib in the NP28673 and NP28761 trials (8.3 months n = 225]) [34]. However, results for rwPFS for second‐line brigatinib and crizotinib retreatment in our analysis do differ from PFS reported in clinical trials (e.g., 11.32 months [n = 7] for brigatinib in our analysis vs. 16.7 months [n = 110] in the ALTA trial [35]). These differences may occur due to small sample sizes in the database.

Similar to results from previously conducted studies of real‐world treatment patterns for ALK+ NSCLC [25, 26, 36–39], we found that crizotinib was the most commonly prescribed first‐line ALK TKI therapy in clinical practice. In the second‐line ALK TKI setting (post crizotinib), our results showed that ceritinib was the most commonly prescribed therapy, which is consistent with the approval timelines and similar to the results of other real‐world studies [24, 25, 37–42]. These results are not surprising, as crizotinib was initially approved by the FDA in 2011 and was the first commercially available ALK TKI therapy in the U.S. [43]. However, the data captured during our study period (January 2011 through June 2018) may not clearly reflect current real‐world treatment patterns, as most data were collected prior to the FDA's 2017 expansion of alectinib and ceritinib's indications to the first‐line setting [44, 45] and initial approval of brigatinib in the post crizotinib setting [15, 46]. Indeed, crizotinib may no longer be the most commonly administered first‐line ALK TKI therapy [47, 48]. The use of alectinib as first‐line ALK TKI therapy has increased considerably since release of the first‐line trial results [28, 49, 50]. Although ceritinib is also approved in the first‐line setting, the incidence of gastrointestinal toxicity seen in the trials may limit its use [19, 51]. Brigatinib has shown superior PFS compared with crizotinib in the first‐line setting [18] but was not approved by the FDA for first‐line use during the analysis period. Although the time frame between the 2017 FDA approvals and our data cutoff comprised a relatively small proportion of our study period, we did find some evidence in our analysis of first‐line use of alectinib and ceritinib and, to a lesser extent, second‐line use of brigatinib post crizotinib, but the more common use of older treatments shows a persistent unmet need for newer‐generation treatments for ALK+ NSCLC.

We included TTD in our analysis because patients rarely discontinue targeted therapies because of toxicity (unlike chemotherapy). Results of a pooled analysis of eight randomized controlled trials evaluating chemotherapy, TKIs, or immune checkpoint inhibitors in patients with metastatic NSCLC showed that TTD is correlated with PFS in this population [52]. The median TTD in our analysis for patients receiving any first‐line ALK TKI (7.04 months) is similar to our results for median rwPFS (7.47 months). The similarity between TTD and rwPFS in our real‐world study reflects the potential for TTD to be a meaningful clinical endpoint.

Our results showed that progression occurs earlier in patients with brain metastasis. Results from previous real‐world studies show substantial economic burden for patients with ALK+ NSCLC with brain metastasis. A retrospective U.S. claims database analysis reported that costs and health care resource use for crizotinib‐treated patients with ALK+ NSCLC increased substantially after the disease metastasized to the brain [53]. Results from a U.S. claims database analysis conducted by Burudpakdee et al. showed a mean incremental cost for brain metastasis of $6,092 per patient per month (32.3% higher than for patients without brain metastasis) [54]. These economic analyses suggest that using next‐generation ALK TKIs (i.e., ceritinib, alectinib, brigatinib) rather than crizotinib could produce cost savings in addition to improving patient outcomes.

Strengths and Limitations

Using the Flatiron Health EHR database's machine learning and curation technique, we determined rwPFS in a large population (n = 581) of patients with advanced ALK+ NSCLC. Our results provide insights into the real‐world treatment of patients with advanced ALK+ NSCLC in U.S. oncology practices as well as the potential unmet needs with current ALK TKI therapies.

Our analysis does have some obvious limitations. First, PFS based on radiological progression is not as consistently or frequently assessed in the real‐world setting as in clinical trials. Limitations of the Flatiron Health EHR‐derived deidentified database include a lack of some clinically relevant data, such as consistent and robust information on performance status, comorbidities, and adverse events as well as complete information on radiation treatments and surgery. An EHR‐derived database is bound to have a degree of missing data, as the information is available insofar as it is documented in the EHR and, in this case, in the EHR within the network that feeds the database. Therefore, information on interventions that happen outside of that network, or documentation of response, performance status, comorbidities, and/or adverse events, may be incomplete. As mentioned before, we used data from January 2011 through June 2018, so our results may not represent current real‐world treatment patterns. However, our results did show use of ceritinib and alectinib for first‐line ALK therapy and brigatinib for second‐line ALK therapy, which may reflect when the drugs were approved by the FDA, demonstrating that the database could reflect this type of change. Few patients in our analysis received a next‐generation ALK TKI as first‐line ALK TKI therapy: only 80 patients received first‐line alectinib and 9 patients received first‐line ceritinib in our analysis, and therefore results from our study comparing first and second lines of ALK TKI therapies should be viewed cautiously, with the recognition that crizotinib is no longer appropriate as a first‐line ALK TKI therapy, at least in the U.S.

Additional studies are needed to evaluate the role of next‐generation agents when used as first‐line ALK TKI therapy. As the roles of next‐generation ALK TKI therapies evolve from second‐ to first‐line ALK TKI therapy, additional analyses will be needed to address the optimal sequence of therapy in patients with advanced ALK+ NSCLC. In that regard, additional clinical trials and other efforts will shed some light on appropriate sequencing, give insights into mechanisms of resistance, and improve our understanding and approach in this space of ALK‐directed therapies.

Conclusion

Results from this analysis highlight some of the unmet treatment needs for patients with advanced ALK+ NSCLC. In the real world, median rwPFS and TTD are short in patients with advanced ALK+ NSCLC, and pre‐existing brain metastasis was associated with a significantly higher risk of progression. These findings support the need for more effective treatments for ALK+ NSCLC, especially for patients with baseline brain metastasis and, by providing some real‐world data on the use of next‐generation ALK TKIs in the first‐line ALK TKI setting, may help inform future clinical trial designs addressing the optimal sequence of therapy in this population.

Acknowledgements

The authors thank Beth Lesher, PharmD, BCPS, and Catherine Mirvis, BA, of Pharmerit International for their assistance in writing the manuscript. This support was funded by Millennium Pharmaceuticals, Inc.

This study was funded by Millennium Pharmaceuticals, Inc.

Author Contributions

Conception/design: Mohammad Jahanzeb, Huamao M. Lin

Collection and/or assembly of data: Yu Yin

Data analysis and interpretation: Mohammad Jahanzeb, Huamao M. Lin, Xiaoyun Pan, Yu Yin, Yanyu Wu, Beth Nordstrom, Mark A. Socinski

Manuscript writing: Mohammad Jahanzeb, Huamao M. Lin, Xiaoyun Pan, Yu Yin, Yanyu Wu, Beth Nordstrom, Mark A. Socinski

Final approval of manuscript: Mohammad Jahanzeb, Huamao M. Lin, Xiaoyun Pan, Yu Yin, Yanyu Wu, Beth Nordstrom, Mark A. Socinski

Disclosures

Mohammad Jahanzeb: Genentech/Roche, Pfizer, Takeda (C/A, H), Takeda (C/A, H, SAB); Huamao M. Lin: Millennium Pharmaceuticals, Inc. (E); Xiaoyun Pan: Millennium Pharmaceuticals, Inc. (E); Yu Yin: Millennium Pharmaceuticals, Inc. (E); Yanyu Wu: Millennium Pharmaceuticals, Inc. (E); Beth Nordstrom: Evidera (RF, E‐received funding from Takeda). The other authors indicated no financial relationships.

(C/A) Consulting/advisory relationship; (RF) Research funding; (E) Employment; (ET) Expert testimony; (H) Honoraria received; (OI) Ownership interests; (IP) Intellectual property rights/inventor/patent holder; (SAB) Scientific advisory board

References

Author notes