Cancer Epidemiology 39 (2015) 307–312
Contents lists available at ScienceDirect
Cancer Epidemiology The International Journal of Cancer Epidemiology, Detection, and Prevention journal homepage: www.cancerepidemiology.net
ALK rearrangement testing and treatment patterns for patients with ALK-positive non-small cell lung cancer Annie Gue´rin a,*, Medha Sasane b, Jie Zhang b, Alexander R. Macalalad c, Philip Galebach c, John Jarvis c, Andrew Kageleiry c, Kenneth Culver b, Eric Q. Wu c, Heather Wakelee d a
Group d’analyse, Lte´e, Montre´al, Quebec, Canada Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA Analysis Group, Inc., Boston, MA, USA d Stanford University School of Medicine, Palo Alto, CA, USA b c
A R T I C L E I N F O
A B S T R A C T
Article history: Received 8 November 2014 Received in revised form 17 March 2015 Accepted 8 April 2015 Available online 23 April 2015
Introduction: Approximately 2–8% of non-small cell lung cancer (NSCLC) patients have rearrangements in the anaplastic lymphoma kinase gene (ALK). ALK-targeted therapy is available to patients with tumors known to be ALK+. This chart review study described characteristics of patients with ALK+ NSCLC, patterns of ALK testing and subsequent treatments, and oncologists’ experience with ALK testing in the US. Methods: US oncologists provided information in September and October of 2013 on patients from their practice diagnosed with ALK+ locally advanced or metastatic NSCLC, including the timing of ALK testing and treatment received after testing. Participating oncologists were also surveyed about their experience with ALK testing. Results: 27 oncologists provided data on 273 ALK+ NSCLC patients. Patients’ median age was 67 years upon NSCLC diagnosis. Smoking history varied, with 33% nonsmokers, 33% light smokers, and 33% heavy smokers. Patients were racially diverse: 59% White, 18% Black, 13% Asian, and 10% other. Upon diagnosis of advanced/metastatic NSCLC, patients who were either not tested (19%) or initially tested negative/ inconclusive (1%) all received first-line chemotherapy; the other 219 patients (80%) tested positive, with 133 (61%) receiving an ALK inhibitor and 78 (29%) receiving chemotherapy as first-line treatment. Many oncologists stated being more likely to test for ALK rearrangements among Asians, nonsmokers, and light smokers. Conclusions: In this sample, ALK+ NSCLC patients were racially diverse with mixed smoking history. One in five patients were not tested before first-line therapy. Oncologists reported being more likely to consider ALK testing for patients with particular smoking and race characteristics. ß 2015 Elsevier Ltd. All rights reserved.
Keywords: Lung neoplasms Carcinoma, Non-small-cell lung Anaplastic lymphoma kinase In situ hybridization, Fluorescence
1. Introduction1 Recent advances have identified effective molecular targets that can be present in patients with non-small cell lung cancer [1]. One such target is the oncogenic chimeric protein EML4-ALK that arises from the genetic rearrangement of the anaplastic lymphoma kinase gene (ALK) and the echinoderm microtubule-associated protein-like 4 gene (EML4), or less common fusion partners [2].
* Corresponding author at: Group d’analyse, Lte´e, 1000 de la Gauchetie`re Ouest, Bureau 1200, Montre´al, Quebec H3B 4W5, Canada. Tel.: +1 514 394 4460; fax: +1 514 394 4461. E-mail address: [email protected] (A. Gue´rin). 1 FISH: Fluorescence in situ hybridization; IHC: Immunohistochemistry; RT-PCR: reverse-transcription polymerase chain reaction; NGS: next-generation sequencing; NSCLC: non-small cell lung cancer. http://dx.doi.org/10.1016/j.canep.2015.04.005 1877-7821/ß 2015 Elsevier Ltd. All rights reserved.
Among patients with metastatic non-small cell lung cancer (NSCLC) and ALK rearrangements, a pivotal Phase III open-label randomized trial showed that patients who received the ALK inhibitor crizotinib had a median progression-free survival (PFS) of 7.7 months compared with 3.0 months for patients who received chemotherapy as second-line therapy [3]. Based on evidence from this trial, crizotinib was the first ALK inhibitor approved in the US for the treatment of ALK-positive metastatic NSCLC patients [4]. Recent data have also shown that crizotinib was associated with a superior response rate and progression-free survival compared to chemotherapy as first-line therapy in patients with ALK-positive NSCLC [5]. More recently, ceritinib has been approved for the treatment of patients with ALK-positive metastatic NSCLC with disease progression on or intolerance to crizotinib [6]. To fully benefit from these targeted therapies,
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however, ALK-positive NSCLC patients need to be identified and treated accordingly. Among NSCLC patients, the overall incidence of ALK-positive NSCLC is estimated to be about 2–13% [2,7–13]. Based on published evidence, ALK-positive NSCLC patients are thought to be younger than other NSCLC patients (median age 50 years vs. 70 years) [14,15]. In addition, never/light smokers and patients with adenocarcinoma histology were more likely to be ALK-positive in a cohort study of selected NSCLC patients [9]. Several methods are available to identify ALK-positive NSCLC patients. Fluorescence in situ hybridization (FISH) is the gold standard to detect ALK gene rearrangements [10]; in the US, it is the only approved test to diagnose ALK-positive NSCLC [16]. Immunohistochemistry (IHC) is a more accessible test that can be used to screen for and identify ALK rearrangements, with positive tests to be confirmed with FISH [17]. Other screening tests use sequencing technologies, such as the reverse-transcription polymerase chain reaction (RT-PCR) or next-generation sequencing (NGS) [18]. The National Comprehensive Cancer Network (NCCN) guidelines recommend using multiplex PCR/NGS to screen for multiple genetic alterations at once, including ALK rearrangements, with FISH as a confirmatory test [19]. With all of these available methods, it is unclear what strategies physicians use to screen NSCLC patients for ALK gene rearrangements, and whether access to testing is a significant barrier to receiving treatment with ALK inhibitors in a timely fashion. To gain more insight into the identification and treatment of ALK-positive NSCLC patients treated in the community, this study aimed to assess (1) the characteristics of ALK-positive locally advanced or metastatic NSCLC patients; (2) when and how they were tested for ALK rearrangements relative to their diagnosis of advanced/metastatic disease and initiation of treatment; (3) their treatments before and after detecting ALK rearrangements; and (4) factors associated with access to ALK testing from community oncologists’ perspective. 2. Methods 2.1. Study design For this retrospective cohort study, data collection forms were designed to collect key data on testing and treatment patterns from patients’ medical records, as well as to explore the experiences of community oncologists with ALK testing. This study did not collect any patient identifying information and was exempted from review by the New England Institutional Review Board. 2.2. Data source In September and October of 2013, US oncologists from a panel of physicians associated with Cardinal Health Specialty Solutions were invited to participate in this study. To select patients for the study, participating physicians were instructed to determine which of their patients met the selection criteria described below and sort them by last name. For each selection, random letters were computergenerated until the participating physician could select an eligible patient whose last name began with that letter. Each participating oncologist was asked to complete a survey about his or her experience with ALK testing and treatment, as well as provide information from the medical records of the patients they selected. 2.3. Patient selection criteria Participating physicians were requested to select patients from their practice who met the following criteria: (1) the patient was
diagnosed with ALK-positive NSCLC, (2) the patient had been diagnosed with locally advanced or metastatic NSCLC before the detection of ALK rearrangements, (3) the patient was at least 18 years of age at the diagnosis of locally advanced or metastatic NSCLC, and (4) the patient was followed by the practice from the primary diagnosis of NSCLC until at least six months after the detection of ALK rearrangements, or until the date of death if the patient died within six months. 2.4. Data collection Patient demographic and clinical information at the time of NSCLC primary diagnosis were collected in September and October of 2013 from patients’ medical records, including age, sex, race/ ethnicity, smoking history, cancer histology, cancer stage, and comorbidities. ALK testing history was also collected, including the date and result of each test. In addition, the patient’s initial and subsequent treatments were collected, including the type of treatment, date of initiation, and date of discontinuation. For patients who had died prior to the study date, the date of death was also collected. To remove identifying information from the data collected, the date of locally advanced or metastatic NSCLC diagnosis was defined as day 0, and all other dates were converted to the number of days before or after day 0. Responding physicians were surveyed about their ALK testing experience, including what common issues they encounter when testing for ALK-positive NSCLC and what reasons did they have for not initially testing for ALK rearrangements. Physicians were also asked about whether they were more likely to test for ALK rearrangements based on patient histology and other characteristics. 2.5. Statistical analyses Binary and categorical variables were summarized by counts and proportions, and continuous variables were summarized by medians and interquartile ranges (IQR). A modified Charlson Comorbidity Index (CCI), modified by excluding lung and other cancers, was calculated from the comorbidity information collected. Treatment pathways relative to ALK testing were summarized in a flow chart. All analyses were conducted using SAS 9.3 (SAS Institute Inc., Cary, NC, USA). 3. Results 3.1. Physician and patient characteristics A total of 27 US oncologists from 25 practices participated in the study. A majority of the physicians had been in practice for at least 10 years (81%), and most were in private practice (89%), with the remainder working in an academic (4%) or institutional setting (7%). About 48% were in a large practice of more than 10 oncologists, with 48% located in the Western region of the US, 33% in the Southern region, 15% in the Northeastern region, and 4% in the Midwestern region. Each physician provided data on a median of 10 patients (IQR 5– 14) who met the selection criteria, for a total of 273 patients. The patients’ demographic and cancer characteristics are summarized in Table 1. The median patients’ age was 67 (IQR 58 – 72) years at the time of diagnosis of locally advanced or metastatic NSCLC. The patient sample was racially and ethnically diverse, with 59% White, 18% Black or African American, 13% Asian, 8% Hispanic, and 2% other. Patients were mostly from the Southern (48%) or Western (41%) regions of the US, and 8% were from the Northeast and 3% from the Midwest. The smoking history was evenly divided (33% for each category) among nonsmokers, light smokers (less than a ten pack-year history), and heavy smokers (at least a ten pack-year
A. Gue´rin et al. / Cancer Epidemiology 39 (2015) 307–312 Table 1 Patient demographic and disease characteristics. Patient (N = 273)
Characteristic
67 (58–72)
Age at locally advanced or metastatic NSCLC diagnosis (years), median (IQR) Male, N (%) Race/ethnicity, N (%) White Black or African American Asian Hispanic or Latino American Indian or Alaskan Native Native Hawaiian or other Pacific Islander Geographic region, (%)a West South Northeast Midwest Smoking history, N (%) Nonsmoker Light smoker Heavy smoker Unknown Modified Charlson Comorbidity Index, N (%) 0–2 3–5 >5 Cancer histology at primary diagnosis, N (%) Adenocarcinoma Mixed Large cell carcinoma Squamous cell carcinoma Cancer stage at primary diagnosis, N (%) Occult carcinoma Stage 0–IB Stage IIA or IIB Stage IIIA Stage IIIB Stage IV Unknown
142 (52) 162 49 36 22 3 1
(59) (18) (13) (8) (1) (0)
112 130 23 8
(41) (48) (8) (3)
90 91 89 3
(33) (33) (33) (1)
198 (73) 65 (24) 10 (4) 222 30 13 8
(81) (11) (5) (3)
0 0 10 7 3 241 12
(0) (0) (4) (3) (1) (88) (4)
a Patients’ geographic region of residence was imputed based on the location (state) of the responding physician’s practice. NSCLC, non-small cell lung cancer; IQR, interquartile range.
history). Aside from their lung cancer, the majority of patients had few comorbidities at the time of the primary NSCLC diagnosis, with 73% having a modified CCI of 0–2. Adenocarcinoma and mixed histology accounted for 81% and 11% of the histology subtypes in this sample, respectively, while large cell carcinoma and squamous cell carcinoma accounted for 5% and 3%, respectively. Most of the patients (88%) already had metastatic disease at the time of the primary NSCLC diagnosis. 3.2. ALK testing and treatments The most commonly used method for testing for ALK rearrangements in these patients was FISH (46%; Table 2). Other Table 2 Testing Methods Used to Detect ALK Rearrangements. Testing method, N (%)
Patients (N = 236a)
FISH PCR IHC IHC + PCR IHC + FISH NGS
108 92 17 13 4 2
(46) (39) (7) (6) (2) (1)
a The information was not available for 37 patients (14% of the patients in the study). FISH, fluorescent in situ hybridization; PCR, polymerase chain reaction; IHC, immunohistochemistry; NGS, next generation sequencing.
309
testing methods frequently used included PCR (39%) and IHC (7%). As shown in Fig. 1, 222 patients (81%) received testing for ALK rearrangements immediately after the diagnosis of advanced or metastatic NSCLC, of whom three (1%) initially tested negative for ALK rearrangements but were found to be ALK-positive in a later test. 51 patients (19%) who were not tested initially received chemotherapy as first-line treatment before they were detected to have ALK rearrangements. Of the 219 patients who initially tested positive for ALK rearrangements after diagnosis, 133 (61%) received an ALK inhibitor and 78 (29%) received chemotherapy as first-line treatment. Overall, all 273 patients eventually tested positive for ALK rearrangements to be eligible for this study, but only 182 patients (67%) received an ALK inhibitor as the next line of treatment after ALK rearrangements were detected. The rest of the patients received chemotherapy or did not receive further antineoplastic treatment. When surveyed about their practice, the 27 participating physicians reported having treated a median of 82 locally advanced or metastatic NSCLC patients in the 12 months prior to the survey and having tested a median of 77% of those patients for ALK rearrangements (Table 3). More than half of the participating physicians (56%) reported that they were more likely to test for ALK rearrangements among patients with the adenocarcinoma subtype; 10 physicians (37%) reported that they were more likely to test for ALK rearrangements among Asians; and 11 physicians (41%) reported that they were more likely to test for ALK rearrangements among nonsmokers and light smokers (Fig. 2). When surveyed about issues they encounter with ALK testing, 17 physicians (63%) cited problems associated with inadequate tissue sample, 11 (41%) cited delays in obtaining test results, and 10 (37%) cited inconclusive test results. Physicians also reported that economic constraints prevented them from treating some of their ALK-positive patients with an ALK inhibitor. 4. Discussion In this study sample of 273 ALK-positive NSCLC patients, the median age was 67 years, which is substantially higher than the age in patients enrolled in the three crizotinib trials and the ceritinib trial, where the median age ranged from 50 to 53 years [14]. Patients in this study were also racially diverse and reflected the diversity of the Western and Southern regions of the US, from which most of the patients were drawn. Also of note, while there was a higher proportion of ALK-positive patients who were nonsmokers or light smokers compared with the overall lung cancer population, one third of patients in this study were heavy smokers [20]. Historically, clinical trial populations of ALK-positive NSCLC patients have included a much higher proportion of Asian patients (29–46%) and nonsmokers (62–72%) than what we observed in this study [3,14]. The reason for the differences of characteristics of patients included in previous studies in the literature and the sample of this study is unknown and deserves further epidemiological exploration, as patient characteristics have been shown to influence physicians’ decision to order ALK testing. Indeed, when surveyed about their experience with ALK testing, many oncologists in this study reported that they were more inclined to order ALK testing for Asian and nonsmoking patients and for patients with adenocarcinoma, perhaps influenced by earlier reported data of higher incidence of ALK rearrangements among patients with these characteristics. This perception, however, may lead to the omission of ALK testing in patients with different characteristics who are ALK-positive. To counter this perception, the NCCN recommends performing ALK testing before initiating first-line treatment for locally advanced or metastatic disease for adenocarcinomas and histologic subtypes other than
A. Gue´rin et al. / Cancer Epidemiology 39 (2015) 307–312
310
First-line testing and treatment patterns
Positive result N=219 (80%)
Third-line testing and treatment patterns
Treated with crizotinib N=133 (49%) Treated with chemotherapy N=78 (29%) No treatment N=8 (3%)
ALK testing N=222 (81%) All Patients N=273 (100%)
Second-line testing and treatment patterns
Negative result N=3 (1%)
Treated with crizotinib N=0 (0%) Treated with chemotherapy N=3 (1%) All 3 patients later received crizotinib following ALK+ test ALK testing N=45 (17%)
Treated with chemo therapy N=51 (19%)
No ALK testing N=6 (2%)
Treated with crizotinib N=40 (15%) Treated with chemotherapy N=2 (1%) Positive result N=45 (17%)
No treatment N=3 (1%)
Treated with crizotinib N=0 (0%) Treated with chemotherapy N=6 (2%)
Tested ALK and treated with crizotinib third-line N=3 (1%) Treated with chemotherapy third-line. Tested ALK+ and treated with crizotinib fourth-line N=3 (1%)
Fig. 1. ALK genetic testing and subsequent treatment patterns.
squamous cell carcinoma regardless of age, race, and smoking history [19]. Even for squamous cell carcinoma patients, the NCCN guidelines recommend considering ALK testing, especially if small biopsy specimens were used to assess histology, if mixed histology was reported, or if patients were never smokers [19]. In this study, only patients who were tested for ALK rearrangements and who had a positive test were selected. Among these patients, approximately one in five patients did not
Table 3 Physicians’ Experience with ALK Testing. Questions
Physician responses (N = 27)
How many patients with locally advanced or metastatic NSCLC have you followed in the past 12 months? Median (IQR) Among the above, how many patients were tested for ALK rearrangements? Median (IQR) How many were tested positive for ALK rearrangements? Median (IQR) What issues, if any, have come up when trying to test for ALK-activated NSCLC?a N (%) Inadequate tissue sample Delay in reporting of results Inconclusive results Prohibitive cost/inadequate insurance coverage Problems related to sample preparation Problems related to sample shipping Problems related to sample storage Getting false negative test result I have not had any issues come up
82 (50–150)
a Categories were not mutually exclusive. IQR, interquartile range; NSCLC, non-small cell lung cancer.
55 (40–115)
8 (3–15)
17 11 10 4 4 4 1 1 7
(63) (41) (37) (15) (15) (15) (4) (4) (26)
receive ALK testing in time to guide the initial therapy for locally advanced or metastatic NSCLC. In addition, one-third of patients did not receive an ALK inhibitor as the next line of therapy after testing positive for ALK rearrangements, even if such therapy was available on the market. Interestingly, over one-third of patients were tested with PCR rather than the FISH test. Of these patients, 89% were also tested for EGFR (data not shown) suggesting that the oncologists may have used PCR to test for multiple genetic abnormalities at once. Oncologists reported issues with ALK testing, such as inadequate tissue sample, delayed results, and inconclusive results, which might have hindered the timely utilization of ALK testing. Since this is an evolving field, replicating this study could help understand how physician practice, as it relates to the diagnosis and treatment of ALKpositive NSCLC patients, has been changing with the evolving landscape. Although efforts were made to recruit physicians across the country to obtain a representative sample of patients, the degree to which their clinical decisions and patterns represent the practice of a wider clinical practice could not be determined. Collectively, these oncologists reported 2032 of their patients had been tested for ALK rearrangements, of whom 283 (13.9%) were positive, which is on the high end of the range of estimates in the literature. It is possible that through referrals these oncologists had a higher percentage of ALK-positive patients than oncologists in general. In addition, because of the retrospective nature of the study, patient information collected through respondents’ chart review may not be complete. Finally, since NSCLC patients were required to be ALKpositive to be eligible for this study, the selected sample reflects the population of ALK-positive NSCLC patients tested, which could be very different from the overall population of ALK-positive NSCLC patients, especially if physicians are more likely to test patients with specific characteristics.
A. Gue´rin et al. / Cancer Epidemiology 39 (2015) 307–312
311
Likelihood of Testing Histology Subtypes 22%
Adenocarcinoma
22%
56%
44%
Large cell
44%
11%
85%
Squamous cell
15%
Likelihood of Testing Other Patient Characteristics Never or light smoker
30%
30%
33%
Asian
30%
41%
Female
0%
10%
22%
59%
26%
Caucasian
37% 37%
30%
Age less than 55
41%
11%
63% 20%
30%
40% Less Likely
50% 60% Equally Likely
11% 70% More Likely
80%
90%
100%
Fig. 2. Physicians’ likelihood to consider ALK rearrangements testing based on histology subtypes and patient characteristics. Scores were reported on an 11-point scale, where 0 is Least Likely and 10 is Most Likely. ‘‘Less Likely’’ includes scores of 0–2; ‘‘Equally Likely’’ includes scores from 3–7; and ‘‘More Likely’’ includes scores from 8–10.
5. Conclusion In this retrospective chart review study conducted among a group of US oncologists, patients with ALK-positive NSCLC were older and more racially diverse with mixed smoking histories than previously documented. Notably, there were documented cases of ALK rearrangements in patients with large cell and squamous cell histology. Oncologists participating in the study reported being more likely to test patients with certain characteristics despite NCCN guidelines to the contrary. Further analyses in a larger, geographically diverse sample of patients would be required to confirm these findings, but they do provide evidence to question the concept that typical ALK-positive NSCLC patients are neversmoking, young Asian patients, and suggest the need to increase molecular testing for all newly diagnosed advanced stage NSCLC patients. Authorship contribution Conception/design: Annie Gue´rin, Medha Sasane, Jie Zhang, Alexander R. Macalalad, Philip Galebach, John Jarvis, Andrew Kageleiry, Kenneth Culver, Eric Q. Wu, Heather Wakelee. Collection and/or assembly of data: Annie Gue´rin, Alexander R. Macalalad, Philip Galebach, John Jarvis, Andrew Kageleiry. Data analysis and interpretation: Annie Gue´rin, Medha Sasane, Jie Zhang, Alexander R. Macalalad, Philip Galebach, John Jarvis, Andrew Kageleiry, Eric Q. Wu, Heather Wakelee. Manuscript writing: Annie Gue´rin, Medha Sasane, Jie Zhang, Alexander R. Macalalad, Philip Galebach, John Jarvis, Andrew Kageleiry, Eric Q. Wu, Heather Wakelee. Final approval of manuscript: Annie Gue´rin, Medha Sasane, Jie Zhang, Alexander R. Macalalad, Philip Galebach, John Jarvis, Andrew Kageleiry, Kenneth Culver, Eric Q. Wu, Heather Wakelee. Conflicts of interest AG, ARM, PG, JJ, AK, and EQW have disclosed that they are employees of Analysis Group, Inc., a company that received funding from Novartis Pharmaceuticals Corporation to conduct this study. MS, JZ, and KC have disclosed that they are employees of Novartis Pharmaceuticals Corporation. HW has received research
funding from Novartis Pharmaceuticals Corporation for conduct of clinical trials, but acted as an uncompensated consultant on this project.
Source of funding Research was funded by Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA. Acknowledgements We thank Jun Yan, an employee of Jun Yan Medical Writing, who contributed to the editing of the manuscript. References [1] Kris MG, Johnson BE, Berry LD, Kwiatkowski DJ, Iafrate AJ, Wistuba II, et al. Using multiplexed assays of oncogenic drivers in lung cancers to select targeted drugs. JAMA 2014;311(19):1998–2006. [2] Soda M, Choi YL, Enomoto M, Takada S, Yamashita Y, Ishikawa S, et al. Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature 2007;448(August (7153)):561–6. [3] Shaw AT, Kim DW, Nakagawa K, Seto T, Crino L, Ahn MJ, et al. Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. N Engl J Med 2013; 368(June (25)):2385–94. [4] http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ ucm376058.htm. Accessed 5/14/2014. [5] Mok TD-WK, Yi-Long W, Benjamin S, Kazuhiko N, Tarek M, Enriqueta F, et al. First-line crizotinib versus pemetrexed – cisplatin or pemetrexed – carboplatin in patients (pts) with advanced ALK-positive non-squamous non-small cell lung cancer (NSCLC): results of a phase III study (PROFILE 1014). J Clin Oncol 2014;32(suppl; abstr 8002):5s. [6] Zykadia (ceritinib) Capsules, oral [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2014. [7] Koivunen JP, Mermel C, Zejnullahu K, Murphy C, Lifshits E, Holmes AJ, et al. EML4-ALK fusion gene and efficacy of an ALK kinase inhibitor in lung cancer. Clin Cancer Res 1 2008;14(July (13)):4275–83. [8] Boland JM, Erdogan S, Vasmatzis G, Yang P, Tillmans LS, Johnson MR, et al. Anaplastic lymphoma kinase immunoreactivity correlates with ALK gene rearrangement and transcriptional up-regulation in non-small cell lung carcinomas. Hum Pathol 2009;40(August (8)):1152–8. [9] Shaw AT, Yeap BY, Mino-Kenudson M, Digumarthy SR, Costa DB, Heist RS, et al. Clinical features and outcome of patients with non-small-cell lung cancer who harbor EML4-ALK. J Clin Oncol 2009;27(September (26)):4247–53. [10] Perner S, Wagner PL, Demichelis F, Mehra R, Lafargue CJ, Moss BJ, et al. EML4ALK fusion lung cancer: a rare acquired event. Neoplasia 2008;10(March (3)): 298–302.
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©2015 Elsevier
Contents lists available at ScienceDirect
Cancer Epidemiology The International Journal of Cancer Epidemiology, Detection, and Prevention journal homepage: www.cancerepidemiology.net
ALK rearrangement testing and treatment patterns for patients with ALK-positive non-small cell lung cancer Annie Gue´rin a,*, Medha Sasane b, Jie Zhang b, Alexander R. Macalalad c, Philip Galebach c, John Jarvis c, Andrew Kageleiry c, Kenneth Culver b, Eric Q. Wu c, Heather Wakelee d a
Group d’analyse, Lte´e, Montre´al, Quebec, Canada Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA Analysis Group, Inc., Boston, MA, USA d Stanford University School of Medicine, Palo Alto, CA, USA b c
A R T I C L E I N F O
A B S T R A C T
Article history: Received 8 November 2014 Received in revised form 17 March 2015 Accepted 8 April 2015 Available online 23 April 2015
Introduction: Approximately 2–8% of non-small cell lung cancer (NSCLC) patients have rearrangements in the anaplastic lymphoma kinase gene (ALK). ALK-targeted therapy is available to patients with tumors known to be ALK+. This chart review study described characteristics of patients with ALK+ NSCLC, patterns of ALK testing and subsequent treatments, and oncologists’ experience with ALK testing in the US. Methods: US oncologists provided information in September and October of 2013 on patients from their practice diagnosed with ALK+ locally advanced or metastatic NSCLC, including the timing of ALK testing and treatment received after testing. Participating oncologists were also surveyed about their experience with ALK testing. Results: 27 oncologists provided data on 273 ALK+ NSCLC patients. Patients’ median age was 67 years upon NSCLC diagnosis. Smoking history varied, with 33% nonsmokers, 33% light smokers, and 33% heavy smokers. Patients were racially diverse: 59% White, 18% Black, 13% Asian, and 10% other. Upon diagnosis of advanced/metastatic NSCLC, patients who were either not tested (19%) or initially tested negative/ inconclusive (1%) all received first-line chemotherapy; the other 219 patients (80%) tested positive, with 133 (61%) receiving an ALK inhibitor and 78 (29%) receiving chemotherapy as first-line treatment. Many oncologists stated being more likely to test for ALK rearrangements among Asians, nonsmokers, and light smokers. Conclusions: In this sample, ALK+ NSCLC patients were racially diverse with mixed smoking history. One in five patients were not tested before first-line therapy. Oncologists reported being more likely to consider ALK testing for patients with particular smoking and race characteristics. ß 2015 Elsevier Ltd. All rights reserved.
Keywords: Lung neoplasms Carcinoma, Non-small-cell lung Anaplastic lymphoma kinase In situ hybridization, Fluorescence
1. Introduction1 Recent advances have identified effective molecular targets that can be present in patients with non-small cell lung cancer [1]. One such target is the oncogenic chimeric protein EML4-ALK that arises from the genetic rearrangement of the anaplastic lymphoma kinase gene (ALK) and the echinoderm microtubule-associated protein-like 4 gene (EML4), or less common fusion partners [2].
* Corresponding author at: Group d’analyse, Lte´e, 1000 de la Gauchetie`re Ouest, Bureau 1200, Montre´al, Quebec H3B 4W5, Canada. Tel.: +1 514 394 4460; fax: +1 514 394 4461. E-mail address: [email protected] (A. Gue´rin). 1 FISH: Fluorescence in situ hybridization; IHC: Immunohistochemistry; RT-PCR: reverse-transcription polymerase chain reaction; NGS: next-generation sequencing; NSCLC: non-small cell lung cancer. http://dx.doi.org/10.1016/j.canep.2015.04.005 1877-7821/ß 2015 Elsevier Ltd. All rights reserved.
Among patients with metastatic non-small cell lung cancer (NSCLC) and ALK rearrangements, a pivotal Phase III open-label randomized trial showed that patients who received the ALK inhibitor crizotinib had a median progression-free survival (PFS) of 7.7 months compared with 3.0 months for patients who received chemotherapy as second-line therapy [3]. Based on evidence from this trial, crizotinib was the first ALK inhibitor approved in the US for the treatment of ALK-positive metastatic NSCLC patients [4]. Recent data have also shown that crizotinib was associated with a superior response rate and progression-free survival compared to chemotherapy as first-line therapy in patients with ALK-positive NSCLC [5]. More recently, ceritinib has been approved for the treatment of patients with ALK-positive metastatic NSCLC with disease progression on or intolerance to crizotinib [6]. To fully benefit from these targeted therapies,
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however, ALK-positive NSCLC patients need to be identified and treated accordingly. Among NSCLC patients, the overall incidence of ALK-positive NSCLC is estimated to be about 2–13% [2,7–13]. Based on published evidence, ALK-positive NSCLC patients are thought to be younger than other NSCLC patients (median age 50 years vs. 70 years) [14,15]. In addition, never/light smokers and patients with adenocarcinoma histology were more likely to be ALK-positive in a cohort study of selected NSCLC patients [9]. Several methods are available to identify ALK-positive NSCLC patients. Fluorescence in situ hybridization (FISH) is the gold standard to detect ALK gene rearrangements [10]; in the US, it is the only approved test to diagnose ALK-positive NSCLC [16]. Immunohistochemistry (IHC) is a more accessible test that can be used to screen for and identify ALK rearrangements, with positive tests to be confirmed with FISH [17]. Other screening tests use sequencing technologies, such as the reverse-transcription polymerase chain reaction (RT-PCR) or next-generation sequencing (NGS) [18]. The National Comprehensive Cancer Network (NCCN) guidelines recommend using multiplex PCR/NGS to screen for multiple genetic alterations at once, including ALK rearrangements, with FISH as a confirmatory test [19]. With all of these available methods, it is unclear what strategies physicians use to screen NSCLC patients for ALK gene rearrangements, and whether access to testing is a significant barrier to receiving treatment with ALK inhibitors in a timely fashion. To gain more insight into the identification and treatment of ALK-positive NSCLC patients treated in the community, this study aimed to assess (1) the characteristics of ALK-positive locally advanced or metastatic NSCLC patients; (2) when and how they were tested for ALK rearrangements relative to their diagnosis of advanced/metastatic disease and initiation of treatment; (3) their treatments before and after detecting ALK rearrangements; and (4) factors associated with access to ALK testing from community oncologists’ perspective. 2. Methods 2.1. Study design For this retrospective cohort study, data collection forms were designed to collect key data on testing and treatment patterns from patients’ medical records, as well as to explore the experiences of community oncologists with ALK testing. This study did not collect any patient identifying information and was exempted from review by the New England Institutional Review Board. 2.2. Data source In September and October of 2013, US oncologists from a panel of physicians associated with Cardinal Health Specialty Solutions were invited to participate in this study. To select patients for the study, participating physicians were instructed to determine which of their patients met the selection criteria described below and sort them by last name. For each selection, random letters were computergenerated until the participating physician could select an eligible patient whose last name began with that letter. Each participating oncologist was asked to complete a survey about his or her experience with ALK testing and treatment, as well as provide information from the medical records of the patients they selected. 2.3. Patient selection criteria Participating physicians were requested to select patients from their practice who met the following criteria: (1) the patient was
diagnosed with ALK-positive NSCLC, (2) the patient had been diagnosed with locally advanced or metastatic NSCLC before the detection of ALK rearrangements, (3) the patient was at least 18 years of age at the diagnosis of locally advanced or metastatic NSCLC, and (4) the patient was followed by the practice from the primary diagnosis of NSCLC until at least six months after the detection of ALK rearrangements, or until the date of death if the patient died within six months. 2.4. Data collection Patient demographic and clinical information at the time of NSCLC primary diagnosis were collected in September and October of 2013 from patients’ medical records, including age, sex, race/ ethnicity, smoking history, cancer histology, cancer stage, and comorbidities. ALK testing history was also collected, including the date and result of each test. In addition, the patient’s initial and subsequent treatments were collected, including the type of treatment, date of initiation, and date of discontinuation. For patients who had died prior to the study date, the date of death was also collected. To remove identifying information from the data collected, the date of locally advanced or metastatic NSCLC diagnosis was defined as day 0, and all other dates were converted to the number of days before or after day 0. Responding physicians were surveyed about their ALK testing experience, including what common issues they encounter when testing for ALK-positive NSCLC and what reasons did they have for not initially testing for ALK rearrangements. Physicians were also asked about whether they were more likely to test for ALK rearrangements based on patient histology and other characteristics. 2.5. Statistical analyses Binary and categorical variables were summarized by counts and proportions, and continuous variables were summarized by medians and interquartile ranges (IQR). A modified Charlson Comorbidity Index (CCI), modified by excluding lung and other cancers, was calculated from the comorbidity information collected. Treatment pathways relative to ALK testing were summarized in a flow chart. All analyses were conducted using SAS 9.3 (SAS Institute Inc., Cary, NC, USA). 3. Results 3.1. Physician and patient characteristics A total of 27 US oncologists from 25 practices participated in the study. A majority of the physicians had been in practice for at least 10 years (81%), and most were in private practice (89%), with the remainder working in an academic (4%) or institutional setting (7%). About 48% were in a large practice of more than 10 oncologists, with 48% located in the Western region of the US, 33% in the Southern region, 15% in the Northeastern region, and 4% in the Midwestern region. Each physician provided data on a median of 10 patients (IQR 5– 14) who met the selection criteria, for a total of 273 patients. The patients’ demographic and cancer characteristics are summarized in Table 1. The median patients’ age was 67 (IQR 58 – 72) years at the time of diagnosis of locally advanced or metastatic NSCLC. The patient sample was racially and ethnically diverse, with 59% White, 18% Black or African American, 13% Asian, 8% Hispanic, and 2% other. Patients were mostly from the Southern (48%) or Western (41%) regions of the US, and 8% were from the Northeast and 3% from the Midwest. The smoking history was evenly divided (33% for each category) among nonsmokers, light smokers (less than a ten pack-year history), and heavy smokers (at least a ten pack-year
A. Gue´rin et al. / Cancer Epidemiology 39 (2015) 307–312 Table 1 Patient demographic and disease characteristics. Patient (N = 273)
Characteristic
67 (58–72)
Age at locally advanced or metastatic NSCLC diagnosis (years), median (IQR) Male, N (%) Race/ethnicity, N (%) White Black or African American Asian Hispanic or Latino American Indian or Alaskan Native Native Hawaiian or other Pacific Islander Geographic region, (%)a West South Northeast Midwest Smoking history, N (%) Nonsmoker Light smoker Heavy smoker Unknown Modified Charlson Comorbidity Index, N (%) 0–2 3–5 >5 Cancer histology at primary diagnosis, N (%) Adenocarcinoma Mixed Large cell carcinoma Squamous cell carcinoma Cancer stage at primary diagnosis, N (%) Occult carcinoma Stage 0–IB Stage IIA or IIB Stage IIIA Stage IIIB Stage IV Unknown
142 (52) 162 49 36 22 3 1
(59) (18) (13) (8) (1) (0)
112 130 23 8
(41) (48) (8) (3)
90 91 89 3
(33) (33) (33) (1)
198 (73) 65 (24) 10 (4) 222 30 13 8
(81) (11) (5) (3)
0 0 10 7 3 241 12
(0) (0) (4) (3) (1) (88) (4)
a Patients’ geographic region of residence was imputed based on the location (state) of the responding physician’s practice. NSCLC, non-small cell lung cancer; IQR, interquartile range.
history). Aside from their lung cancer, the majority of patients had few comorbidities at the time of the primary NSCLC diagnosis, with 73% having a modified CCI of 0–2. Adenocarcinoma and mixed histology accounted for 81% and 11% of the histology subtypes in this sample, respectively, while large cell carcinoma and squamous cell carcinoma accounted for 5% and 3%, respectively. Most of the patients (88%) already had metastatic disease at the time of the primary NSCLC diagnosis. 3.2. ALK testing and treatments The most commonly used method for testing for ALK rearrangements in these patients was FISH (46%; Table 2). Other Table 2 Testing Methods Used to Detect ALK Rearrangements. Testing method, N (%)
Patients (N = 236a)
FISH PCR IHC IHC + PCR IHC + FISH NGS
108 92 17 13 4 2
(46) (39) (7) (6) (2) (1)
a The information was not available for 37 patients (14% of the patients in the study). FISH, fluorescent in situ hybridization; PCR, polymerase chain reaction; IHC, immunohistochemistry; NGS, next generation sequencing.
309
testing methods frequently used included PCR (39%) and IHC (7%). As shown in Fig. 1, 222 patients (81%) received testing for ALK rearrangements immediately after the diagnosis of advanced or metastatic NSCLC, of whom three (1%) initially tested negative for ALK rearrangements but were found to be ALK-positive in a later test. 51 patients (19%) who were not tested initially received chemotherapy as first-line treatment before they were detected to have ALK rearrangements. Of the 219 patients who initially tested positive for ALK rearrangements after diagnosis, 133 (61%) received an ALK inhibitor and 78 (29%) received chemotherapy as first-line treatment. Overall, all 273 patients eventually tested positive for ALK rearrangements to be eligible for this study, but only 182 patients (67%) received an ALK inhibitor as the next line of treatment after ALK rearrangements were detected. The rest of the patients received chemotherapy or did not receive further antineoplastic treatment. When surveyed about their practice, the 27 participating physicians reported having treated a median of 82 locally advanced or metastatic NSCLC patients in the 12 months prior to the survey and having tested a median of 77% of those patients for ALK rearrangements (Table 3). More than half of the participating physicians (56%) reported that they were more likely to test for ALK rearrangements among patients with the adenocarcinoma subtype; 10 physicians (37%) reported that they were more likely to test for ALK rearrangements among Asians; and 11 physicians (41%) reported that they were more likely to test for ALK rearrangements among nonsmokers and light smokers (Fig. 2). When surveyed about issues they encounter with ALK testing, 17 physicians (63%) cited problems associated with inadequate tissue sample, 11 (41%) cited delays in obtaining test results, and 10 (37%) cited inconclusive test results. Physicians also reported that economic constraints prevented them from treating some of their ALK-positive patients with an ALK inhibitor. 4. Discussion In this study sample of 273 ALK-positive NSCLC patients, the median age was 67 years, which is substantially higher than the age in patients enrolled in the three crizotinib trials and the ceritinib trial, where the median age ranged from 50 to 53 years [14]. Patients in this study were also racially diverse and reflected the diversity of the Western and Southern regions of the US, from which most of the patients were drawn. Also of note, while there was a higher proportion of ALK-positive patients who were nonsmokers or light smokers compared with the overall lung cancer population, one third of patients in this study were heavy smokers [20]. Historically, clinical trial populations of ALK-positive NSCLC patients have included a much higher proportion of Asian patients (29–46%) and nonsmokers (62–72%) than what we observed in this study [3,14]. The reason for the differences of characteristics of patients included in previous studies in the literature and the sample of this study is unknown and deserves further epidemiological exploration, as patient characteristics have been shown to influence physicians’ decision to order ALK testing. Indeed, when surveyed about their experience with ALK testing, many oncologists in this study reported that they were more inclined to order ALK testing for Asian and nonsmoking patients and for patients with adenocarcinoma, perhaps influenced by earlier reported data of higher incidence of ALK rearrangements among patients with these characteristics. This perception, however, may lead to the omission of ALK testing in patients with different characteristics who are ALK-positive. To counter this perception, the NCCN recommends performing ALK testing before initiating first-line treatment for locally advanced or metastatic disease for adenocarcinomas and histologic subtypes other than
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310
First-line testing and treatment patterns
Positive result N=219 (80%)
Third-line testing and treatment patterns
Treated with crizotinib N=133 (49%) Treated with chemotherapy N=78 (29%) No treatment N=8 (3%)
ALK testing N=222 (81%) All Patients N=273 (100%)
Second-line testing and treatment patterns
Negative result N=3 (1%)
Treated with crizotinib N=0 (0%) Treated with chemotherapy N=3 (1%) All 3 patients later received crizotinib following ALK+ test ALK testing N=45 (17%)
Treated with chemo therapy N=51 (19%)
No ALK testing N=6 (2%)
Treated with crizotinib N=40 (15%) Treated with chemotherapy N=2 (1%) Positive result N=45 (17%)
No treatment N=3 (1%)
Treated with crizotinib N=0 (0%) Treated with chemotherapy N=6 (2%)
Tested ALK and treated with crizotinib third-line N=3 (1%) Treated with chemotherapy third-line. Tested ALK+ and treated with crizotinib fourth-line N=3 (1%)
Fig. 1. ALK genetic testing and subsequent treatment patterns.
squamous cell carcinoma regardless of age, race, and smoking history [19]. Even for squamous cell carcinoma patients, the NCCN guidelines recommend considering ALK testing, especially if small biopsy specimens were used to assess histology, if mixed histology was reported, or if patients were never smokers [19]. In this study, only patients who were tested for ALK rearrangements and who had a positive test were selected. Among these patients, approximately one in five patients did not
Table 3 Physicians’ Experience with ALK Testing. Questions
Physician responses (N = 27)
How many patients with locally advanced or metastatic NSCLC have you followed in the past 12 months? Median (IQR) Among the above, how many patients were tested for ALK rearrangements? Median (IQR) How many were tested positive for ALK rearrangements? Median (IQR) What issues, if any, have come up when trying to test for ALK-activated NSCLC?a N (%) Inadequate tissue sample Delay in reporting of results Inconclusive results Prohibitive cost/inadequate insurance coverage Problems related to sample preparation Problems related to sample shipping Problems related to sample storage Getting false negative test result I have not had any issues come up
82 (50–150)
a Categories were not mutually exclusive. IQR, interquartile range; NSCLC, non-small cell lung cancer.
55 (40–115)
8 (3–15)
17 11 10 4 4 4 1 1 7
(63) (41) (37) (15) (15) (15) (4) (4) (26)
receive ALK testing in time to guide the initial therapy for locally advanced or metastatic NSCLC. In addition, one-third of patients did not receive an ALK inhibitor as the next line of therapy after testing positive for ALK rearrangements, even if such therapy was available on the market. Interestingly, over one-third of patients were tested with PCR rather than the FISH test. Of these patients, 89% were also tested for EGFR (data not shown) suggesting that the oncologists may have used PCR to test for multiple genetic abnormalities at once. Oncologists reported issues with ALK testing, such as inadequate tissue sample, delayed results, and inconclusive results, which might have hindered the timely utilization of ALK testing. Since this is an evolving field, replicating this study could help understand how physician practice, as it relates to the diagnosis and treatment of ALKpositive NSCLC patients, has been changing with the evolving landscape. Although efforts were made to recruit physicians across the country to obtain a representative sample of patients, the degree to which their clinical decisions and patterns represent the practice of a wider clinical practice could not be determined. Collectively, these oncologists reported 2032 of their patients had been tested for ALK rearrangements, of whom 283 (13.9%) were positive, which is on the high end of the range of estimates in the literature. It is possible that through referrals these oncologists had a higher percentage of ALK-positive patients than oncologists in general. In addition, because of the retrospective nature of the study, patient information collected through respondents’ chart review may not be complete. Finally, since NSCLC patients were required to be ALKpositive to be eligible for this study, the selected sample reflects the population of ALK-positive NSCLC patients tested, which could be very different from the overall population of ALK-positive NSCLC patients, especially if physicians are more likely to test patients with specific characteristics.
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Likelihood of Testing Histology Subtypes 22%
Adenocarcinoma
22%
56%
44%
Large cell
44%
11%
85%
Squamous cell
15%
Likelihood of Testing Other Patient Characteristics Never or light smoker
30%
30%
33%
Asian
30%
41%
Female
0%
10%
22%
59%
26%
Caucasian
37% 37%
30%
Age less than 55
41%
11%
63% 20%
30%
40% Less Likely
50% 60% Equally Likely
11% 70% More Likely
80%
90%
100%
Fig. 2. Physicians’ likelihood to consider ALK rearrangements testing based on histology subtypes and patient characteristics. Scores were reported on an 11-point scale, where 0 is Least Likely and 10 is Most Likely. ‘‘Less Likely’’ includes scores of 0–2; ‘‘Equally Likely’’ includes scores from 3–7; and ‘‘More Likely’’ includes scores from 8–10.
5. Conclusion In this retrospective chart review study conducted among a group of US oncologists, patients with ALK-positive NSCLC were older and more racially diverse with mixed smoking histories than previously documented. Notably, there were documented cases of ALK rearrangements in patients with large cell and squamous cell histology. Oncologists participating in the study reported being more likely to test patients with certain characteristics despite NCCN guidelines to the contrary. Further analyses in a larger, geographically diverse sample of patients would be required to confirm these findings, but they do provide evidence to question the concept that typical ALK-positive NSCLC patients are neversmoking, young Asian patients, and suggest the need to increase molecular testing for all newly diagnosed advanced stage NSCLC patients. Authorship contribution Conception/design: Annie Gue´rin, Medha Sasane, Jie Zhang, Alexander R. Macalalad, Philip Galebach, John Jarvis, Andrew Kageleiry, Kenneth Culver, Eric Q. Wu, Heather Wakelee. Collection and/or assembly of data: Annie Gue´rin, Alexander R. Macalalad, Philip Galebach, John Jarvis, Andrew Kageleiry. Data analysis and interpretation: Annie Gue´rin, Medha Sasane, Jie Zhang, Alexander R. Macalalad, Philip Galebach, John Jarvis, Andrew Kageleiry, Eric Q. Wu, Heather Wakelee. Manuscript writing: Annie Gue´rin, Medha Sasane, Jie Zhang, Alexander R. Macalalad, Philip Galebach, John Jarvis, Andrew Kageleiry, Eric Q. Wu, Heather Wakelee. Final approval of manuscript: Annie Gue´rin, Medha Sasane, Jie Zhang, Alexander R. Macalalad, Philip Galebach, John Jarvis, Andrew Kageleiry, Kenneth Culver, Eric Q. Wu, Heather Wakelee. Conflicts of interest AG, ARM, PG, JJ, AK, and EQW have disclosed that they are employees of Analysis Group, Inc., a company that received funding from Novartis Pharmaceuticals Corporation to conduct this study. MS, JZ, and KC have disclosed that they are employees of Novartis Pharmaceuticals Corporation. HW has received research
funding from Novartis Pharmaceuticals Corporation for conduct of clinical trials, but acted as an uncompensated consultant on this project.
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