www.oncotarget.com Oncotarget, 2022, Vol. 13, pp: 812-827 Research Paper Alectinib after failure to crizotinib in patients with ALK‑positive non‑small cell lung cancer: results from the Spanish early access program Reyes Bernabé-Caro1, Pilar Garrido2, Rosario García-Campelo3, Ramón Palmero4, Ángel Artal5, Cristina Bayona6, Delvys Rodríguez-Abreu7, Marta López-Brea8, Alfredo Paredes9, David Vicente10, José Miguel Sánchez Torres11, Margarita Majem12, Pilar Diz13, Rocío Gordo14, Margarita Coca14 and Javier de Castro15 1 Department of Medical Oncology, Hospital Virgen del Rocío, Sevilla, Spain 2 Department of Medical Oncology, Hospital Universitario Ramon y Cajal, Madrid, Spain 3 Department of Medical Oncology, Hospital Universitario A Coruña, A Coruña, Spain 4 Department of Medical Oncology, ICO Bellvitge, Hospitalet Llobregat, Barcelona, Spain 5 Department of Medical Oncology, Hospital Universitario Miguel Servet, Zaragoza, Spain 6 Department of Medical Oncology, Hospital General Yague, Burgos, Spain 7 Department of Medical Oncology, Hospital Insular de Gran Canaria, Las Palmas de Gran Canaria, Spain 8 Department of Medical Oncology, Hospital Marqués de Valdecilla, Santander, Spain 9 Department of Medical Oncology, Hospital Universitario Donostia, Donostia-San Sebastián, Spain 10 Department of Medical Oncology, Hospital Universitario Virgen Macarena, Sevilla, Spain 11 Department of Medical Oncology, Hospital Universitario La Princesa, Madrid, Spain 12 Department of Medical Oncology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain 13 Department of Medical Oncology, Complejo Asistencial Universitario de León, León, Spain 14 Roche Farma, S.A., Madrid, Spain 15 Department of Medical Oncology, Hospital Universitario La Paz, Madrid, Spain Correspondence to: Reyes Bernabé-Caro, email: reyesbernab@yahoo.es Keywords: ALK-positive NSCLC; ALK inhibitor; crizotinib; alectinib; unselected patient Received: April 08, 2022 Accepted: May 19, 2022 Published: June 15, 2022 Copyright: © 2022 Bernabé-Caro et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. ABSTRACT This retrospective observational study analyzed the clinical characteristics, treatment patterns and outcomes of 120 patients with advanced ALK-positive non- small-cell lung cancer (ALK+ NSCLC) according to data collected between November 2019 and October 2020 in 38 Spanish hospitals. Patients had progressed after 1–5 prior treatment lines (which included crizotinib in any prior line) and received subsequent therapy with alectinib in a local expanded access program. Median age was 58.7 years, 50% of patients were female, 64.1% had ECOG PS of 0–1, 85% presented stage IV, 95% had adenocarcinoma histology and 20.8% had brain metastases. After a median 9.6 months of alectinib treatment, objective response rate (ORR) was 54.5%, disease control rate (DCR) was 80%, median progression-free survival (PFS) was 9.4 months and median overall survival (OS) was 24.1 months. Patients with brain metastases achieved an intracranial DCR of 71.4%. Adverse events (AEs) were reported in 35.8% of patients (14.2% of AEs were grade ≥3). Over 40% of patients received some treatment after alectinib, most frequently lorlatinib (65.2%) and brigatinib (32.6%). www.oncotarget.com 812 Oncotarget This study provides information on real-world treatment patterns and confirms the tolerability and prolonged PFS and OS observed with alectinib in clinical trials, in unselected pretreated patients with advanced ALK+ NSCLC. INTRODUCTION alectinib (27.1%), while the incidence of AEs leading to discontinuation was lower with alectinib [11]. Final Rearrangement in the anaplastic lymphoma kinase data from the ALUR trial confirmed the primary analysis (ALK) gene occurs in 2–5% of non-small-cell lung (PFS of 10.9 months with alectinib versus 1.4 months cancer (NSCLC) cases and leads to constitutive activation with chemotherapy [HR: 0.2, 95% CI: 0.12–0.33,; P < of the ALK kinase, which promotes ALK-driven 0.001) [12]. tumorigenesis [1]. ALK-positive NSCLC (ALK+ NSCLC) In the phase III ALEX trial, which compared is characterized by frequent dissemination to the central alectinib with crizotinib as first-line treatment in 303 nervous system (CNS) [2–4]. adult patients with advanced ALK+ NSCLC, alectinib Following its approval in 2011, crizotinib became demonstrated superior PFS, CNS activity, delayed the standard first-line treatment for advanced ALK+ CNS progression and lower toxicity than crizotinib, NSCLC. However, most patients treated with this drug irrespective of prior CNS disease or radiotherapy, or relapsed within 1 year, due mainly to the development type of ALK variant [13, 14]. Updated results from this of crizotinib resistance or poor CNS penetration [5, 6]. trial have confirmed the superior investigator-assessed The median progression-free survival (PFS) with first- PFS, with a median of 34.8 months in the alectinib line crizotinib was 10.9 months [5]. Second-generation arm versus 10.9 months for crizotinib (HR 0.43, 95% ALK inhibitors (such as ceritinib, alectinib and brigatinib) CI; 0.32–0.58) and a 5-year OS rate of 62.5% with emerged and were initially approved for use after alectinib and 45.5% with crizotinib [15–17]. Alectinib crizotinib progression. Ceritinib was approved in 2015 superiority in independent review facility-assessed PFS for use in ALK+ NSCLC patients who had progressed versus crizotinib was confirmed in the Japanese phase on crizotinib. Alectinib is a highly specific ALK tyrosine III J-ALEX clinical trial, in which follow-up continues kinase inhibitor (TKI) that has shown activity against [18, 19]. Results from the phase III ALESIA study of a broad range of mutations responsible for crizotinib first-line alectinib versus crizotinib in Asian patients resistance, and has demonstrated both clinical systemic with advanced ALK+ NSCLC confirmed the clinical and CNS efficacy as well as a good safety profile in benefit of alectinib in the first-line setting [20]. These clinical trials. Pooled data from the 2 pivotal multicenter findings changed the standard of care to alectinib as phase II studies of alectinib (NP28761 and NP28673) [7, front-line therapy for patients with advanced ALK+ 8] in ALK+ NSCLC patients who had progressed on, or NSCLC [21]. were intolerant to, crizotinib, confirmed the efficacy of Significant results obtained from clinical trials alectinib over long follow-up periods [9]. The authors led to the first approval of alectinib for use in patients reported an objective response rate (ORR) of 51.3%, with advanced ALK+ NSCLC who relapsed or were disease control rate (DCR) of 78.8%, median progression- intolerant to crizotinib, and in October 2017, the European free survival (PFS) of 8.3 months and median overall Medicines Agency (EMA) recommended extending the survival (OS) of 29.1 months, with a good safety profile indication for alectinib to treatment-naïve advanced ALK+ [9, 10]. NSCLC patients [22]. The phase III ALUR study, designed to compare Next-generation TKI are listed as the recommended the efficacy and safety of alectinib versus standard first-line therapy for advanced ALK+ NSCLC [23, 24]. chemotherapy in 107 patients previously treated with Indeed, the latest National Comprehensive Cancer platinum-based doublet chemotherapy and crizotinib, Network (NCCN) guidelines recommend the use of showed significantly improved systemic efficacy with alectinib, brigatinib, and lorlatinib as preferred first-line a median investigator-assessed PFS of 9.6 months with treatment options [25]. Overall, next-generation ALK alectinib versus 1.4 months with chemotherapy (hazard TKIs (alectinib, ceritinib, brigatinib) have replaced the ratio [HR]: 0.15, 95% confidence interval [CI]: 0.08– first-generation TKI crizotinib as first-line treatments for 0.29, P < 0.001). Alectinib showed clinically relevant ALK+ NSCLC patients [17]. superiority to chemotherapy for intracranial disease Despite the satisfactory outcomes demonstrated with compared to chemotherapy, along with a favorable alectinib in clinical trials and its extensive use in the first- safety profile. The CNS ORR was significantly higher line setting, there is a lack of real-world data on unselected with alectinib (54.2%) versus chemotherapy (0%; populations, which could help to fill gaps in the literature. P < 0.001). Grade ≥ 3 adverse events (AEs) were In Spain, alectinib has been used after failure to more common with chemotherapy (41.2%) than with crizotinib in advanced ALK+ NSCLC within an expanded www.oncotarget.com 813 Oncotarget access program (EAP). The present REALK study aimed by ceritinib (13.3%) and brigatinib (6.7%) (Supplementary to define this patient population and to assess the treatment Table 1). The mean duration of treatment (DOT) prior patterns used in clinical practice and the associated clinical to alectinib was 9.1 months (95% CI: 7.8–10.3), with a outcomes. median of 7.5 months (IQR: 2.8–14.4). Most patients (86.7%) discontinued prior treatments due to disease RESULTS progression. Indeed, this was the main cause of crizotinib discontinuation (82.5% of patients), although 13.3% of Patient clinical and pathophysiological patients discontinued due to toxicity (Supplementary characterization at diagnosis Table 1). At initiation of alectinib treatment, 12.5%, 8.3% and 18.3% of patients presented altered ALT, AST or GGT All clinical and demographic features were values, respectively; in addition, 3.3% presented abnormal assessed at different time points during the follow-up: at bilirubin values (data not shown). diagnosis of advanced ALK+ NSCLC; during treatments prior to alectinib treatment; at initiation, during and Patient characteristics during follow-up of after alectinib treatment; and after subsequent lines of alectinib treatment treatment. Just over half the patients (55.8%) had died at the time of data collection, mostly due to disease Most patients (84.2%) initiated alectinib treatment progression (91.0%). Table 1 summarizes the patient due to disease progression after failure to previous characteristics at diagnosis. Of 120 patients, 50% treatment lines (Table 2). Mean DOT with alectinib was were female, mostly Caucasian (96.7%). Mean age 13.9 months (95% CI: 11.7–16) with median DOT of at diagnosis of advanced disease was 58.7 years and 9.6 months (IQR: 3.1–25.2) and maximum DOT of 39.2 66.7% of patients were younger than 65 years. Most months. Patients received a median daily dose of alectinib patients were non-smokers (45.8%), while 29.2% of 1200 mg/day (600 mg twice daily as recommended were former smokers and 25% were current smokers. (IQR: 1200–1200) with a minimum dose of 600 mg/ Eighty-five percent of patients had stage IV disease and day (300 mg twice daily). During follow-up of patients 20.8% presented brain metastases. Adenocarcinoma under alectinib treatment, 33.3% presented an ECOG histology was reported in 95% of patients. ECOG PS PS 0, 41.7% had ECOG PS 1 and 8.3% had ECOG 0 or 1 was reported in 25.8% and 38.3% of patients, PS 2 (Table 2). According to the liver function tests, respectively. Diagnosis of ALK translocation was 20.8% to 31.7% of the patients presented altered levels confirmed using fluorescent in situ hybridization of ALT or AST and almost 21% of patients had altered (FISH) or immunohistochemistry in 53.3% and 43.3% GGT or bilirubin values. The main reason for alectinib of patients, respectively. The percentage of patients with discontinuation was disease progression (73.8% of abnormal liver function tests based on altered levels of patients). alanine transaminase (ALT), aspartate transaminase (AST), gamma-glutamyl transferase (GGT) or Patient characteristics after alectinib and bilirubin at diagnosis were 8.3%, 5%, 16.7% and 4.2%, subsequent treatment regimens respectively. Of 120 patients, 46 (38.7%) followed subsequent Patient characteristics and prior treatment treatments after alectinib. In this subset of patients, regimens at initiation of alectinib lorlatinib was the most frequently prescribed therapy (65.2% patients), followed by brigatinib (32.6%) and At initiation of alectinib therapy, 38.3% and 15% chemotherapy (28.3%) (Table 3). One single patient of patients had known ECOG PS 0 and 1, respectively may have simultaneously received more than 1 of these (Table 2). As per protocol, all patients included in the treatments. Mean duration of subsequent treatments after study had been treated with at least one prior line of alectinib was 5.3 months (95% CI: 3.8–6.7) and median crizotinib. Almost half the patients (46.7%) had been DOT was 3.5 months (IQR: 1.7–5), with a maximum treated with only 1 prior treatment line, 38.3% had duration of 18.1 months. The most common reason for received 2 previous treatment lines and 15.1% received treatment discontinuation was disease progression (56.5% ≥3 lines. of patients). ECOG PS was 0 for 26.1% of patients, 1 for In the first and second lines of treatment, crizotinib 39.1%, 2 for 15.2%, and 3 for 6.5% (Table 3). was the preferred therapy (59.2% and 34.2% of patients, respectively) followed by chemotherapy (42.5% and Characterization of metastases and patterns of 8.3% of patients, respectively), while the use of ceritinib disease progression was very limited (5.8% and 4.2%, respectively). After crizotinib, chemotherapy was the most widely used therapy At diagnosis of advanced ALK+ NSCLC, the most (45.8% of patients) in all previous treatment lines, followed common sites of metastases were the lung (50.0%) and www.oncotarget.com 814 Oncotarget Table 1: Demographic and clinical characteristics of patients included in the study at diagnosis of advanced NSCLC Characteristics Total patients (120) Sex, n (%)   Female 60 (50)   Male 60 (50) Age (years)   Mean (SD) 58.7 (12.9)    Median (min, max) 57.5 (49-69) Age distribution at diagnosis, n (%)    < 65 years 80 (66.7)    ≥ 65 years 40 (33.3) Ethnicity, n (%)   Caucasian 116 (96.7)   Non-Caucasian 4 (3.3) Smoking status at diagnosis, n (%)    Active smoker 30 (25)   Former smoker 35 (29.2)   Non-smoker 55 (45.8) Disease stage, n (%)   IIIB 18 (15)    IV 102 (85) Histology, n (%)   Adenocarcinoma 114 (95)    Large cell carcinoma 1 (0.8)   Squamous-cell carcinoma 3 (2.5)   Undifferentiated 1 (0.8)   Other 1 (0.8) ECOG PS at diagnosis, n (%)    ECOG 0 31 (25.8)    ECOG 1 46 (38.3)    ECOG 2 10 (8.3)    ECOG 3 0 (0)    ECOG 4 1 (0.8)   Unknown 32 (26.7) Metastasis at advanced diagnosis, n (%)   Yes 102 (85)   No 18 (15) Brain metastasis at diagnosis, n (%)   Yes 25 (20.8)   No 95 (79.2) * 1 patient with unknown date of ALK-translocation diagnosis. Abbreviations: ECOG PS: ECOG performance status; min: minimum; max: maximum; SD: standard deviation. bone (46.1%), followed by the CNS (24.5%) and liver identified in 41.4% of patients who had received crizotinib (16.7%) (Table 4). prior to alectinib therapy (Table 4). According to the line During treatments prior to alectinib, metastases were of treatment in which crizotinib was used, 44.4% and mostly located in the CNS and lung (45.2% and 44.2% of 36.1% of patients treated with crizotinib in the first and patients, respectively) followed by bone (27.9%) and liver second line, respectively, reported CNS metastases. (22.1%) (Table 4). Mean time to progression with prior During alectinib treatment, 69.4% of patients had treatment lines was 10.7 months (95% CI: 9.13–12.2) distant recurrences (Table 4). Lung metastases were and median time to progression was 9.0 months (IQR: reported in 48.4% of patients, followed by CNS metastases 3.9–16.8) (Supplementary Table 1). CNS metastases were in 38.7% of patients; bone and liver metastases were www.oncotarget.com 815 Oncotarget Table 2: Patient characteristics at initiation and during follow up of alectinib treatment Characteristics Total patients Lines of treatment prior to alectinib, n (%) 120 (100)   1 line 56 (46.7)   2 lines 46 (38.3)   3 lines 8 (6.7)   4 lines 8 (6.7)   5 lines 2 (1.7) Reason for alectinib initiationa, n (%) 120 (100)    Toxicity of previous treatments 14 (11.7)   Disease progression 101 (84.2)   Other 5 (4.2) Total daily dose of alectinib (mg)    Median (min, max) 1,200 (600, 1,200) Duration of alectinib treatmentb (months)    Mean (SD; 95% CI) 13.9 (12.3; 11.7–16)    Median (IQR; min, max) 9.6 (3.1–25.2; 0.2, 39.2) Reason for alectinib discontinuation, n (%) 84 (100)   Toxicity 2 (2.4)   Disease progression 62 (73.8)   Death/Otherc 15 (17.9)/5 (6) Best ECOG PS, n (%) At initiation During treatment    ECOG 0 18 (15) 40 (33.3)    ECOG 1 46 (38.3) 50 (41.7)    ECOG 2 16 (13.3) 10 (8.3)    ECOG 3 2 (1.7) 4 (3.3)    ECOG 4 1 (0.8) 0 (0)   Unknown 37 (30.8) 16 (13.3) a Impaired renal function (1 patient); CNS progression and medical decision (1 patient); Due to a mycetoma, 1 patient was treated with voriconazole, which interacts negatively with crizotinib; Investigator’s criteria (1 patient); Pneumonitis (1 patient); b Difference in months between Start date and End date (for ongoing treatments, date of inclusion/date of exitus/date of last contact has been considered as End date); cClinical disease (1 patient); Resistance mutation (1 patient); Respiratory failure (1 patient); Clinical deterioration (1 patient); Maximum benefit (1 patient). Abbreviations: CI: confidence interval; CNS: central nervous system; ECOG PS: Eastern Cooperative Oncology Group performance status; IQR: interquartile range (25–75); min: minimum; max: maximum; SD: standard deviation. reported in 29.0% and 21.0% of patients, respectively. confirmed in a total of 25 patients at diagnosis, using Progression was confirmed in 79% of patients during magnetic resonance imaging (MRI; 68.0%) or computed the first year and 21% of patients progressed during the axial tomography (CT) (36.0%). second year. Mean time to progression was 7.8 months Most CNS metastases (≥50%) were reported as (95% CI: 6.3–9.3) with a median of 6.4 months (IQR: symptomatic at all analysed time points and as multiple 2.6–10.7) (Table 4). lesions. Leptomeningeal carcinomatosis was very rare at diagnosis, and before initiation of and during alectinib Characterization and management of CNS treatment. However, the presence/absence of leptomeningeal metastases carcinomatosis was not characterized in a high percentage of patients (around 40%), and it was not characterized during CNS metastases were confirmed in a high number subsequent therapies (Supplementary Table 2). of advanced ALK+ NSCLC patients, irrespective of the Approximately 50% of patients with CNS metastases time of analysis (Supplementary Table 2). They were received some type of local treatment for the management www.oncotarget.com 816 Oncotarget Table 3: Characteristics of patients who followed subsequent treatments after alectinib regimen Characteristics Total patients Patients under subsequent treatments Type of treatment, n (%) 120 (100) 48 (100)   Chemotherapy 13 (10.8) 13 (28.3)   Immunotherapya 5 (4.2) 5 (10.9)   Brigatinib 15 (12.5) 15 (32.6)   Lorlatinib 30 (25) 30 (65.2)   Otherb 2 (1.7) 2 (4.3) Best ECOG PS, n (%) 120 (100) 48 (100)    ECOG 0 12 (10) 12 (26.1)    ECOG 1 18 (15) 18 (39.1)    ECOG 2 7 (5.8) 7 (15.2)    ECOG 3 7 (5.8) 3 (6.5)   Unknown 17 (14.2) 17 (37) Reason for discontinuation, n (%)   Toxicity 3 (2.5) 3 (6.5)   Disease progression 26 (21.7) 26 (56.5)   Death 2 (1.7) 2 (4.3)   Otherb 12 (10) 12 (26.1) Duration of treatment, (months)c    Mean (SD; 95% CI) 5.3 (4.8; 3.8–6.7)    Median (IQR; min, max) 3.5 (1.7-7.5; 0.2, 18.1) TTP (months)    Mean (SD; 95% CI) 4.4 (3.3; 3–5.7)    Median (IQR; min, max) 3.7 (1.9–6; 0.9–13.8) Nivolumab (2 patients); Pembrolizumab (2 patients); Atezolizumab (1 patient); bAlectinib (1 patient); crizotinib (1 patient); c a For ongoing treatments, the date of inclusion/date of exitus/date of last contact has been considered as End date. Abbreviations: CI: confidence interval; ECOG PS: ECOG performance status; IQR: interquartile range (25–75); min: minimum; max: maximum; SD: standard deviation; TTP: time to progression. of brain metastasis at diagnosis, during alectinib treatment median DOR was 10.2 months (IQR: 4.4–13.4). Based on and during subsequent therapies (Supplementary Table 2). 10 patients with measurable metastases, ORR was 30.0% Only 29.8% of patients were treated locally for CNS and DCR was 70.0%. Mean time to first response was metastases before alectinib initiation. The most 4.1 months (95% CI: 1.9–6.2) and median time to first common local treatments at diagnosis were whole-brain response was 2.6 months (IQR: 1.3–3.5), with a maximum radiotherapy (WBRT) (50%) or radiosurgery (50%). of 17.1 months. During alectinib treatment, mean time to During alectinib treatment and subsequent lines of first response or to reduction of corticosteroids was 4.1 therapy, radiotherapy was the most common therapeutic ± 4.6 months (95%CI: 1.9–6.2), with a median of 2.6 choice (>60%). The use of corticosteroids was reported in months (IQR: 1.3–3.5) (Supplementary Table 2). 23.2% of patients with CNS metastases at diagnosis, and increased during alectinib treatment (10 out of 12 patients: Secondary outcomes after alectinib use in a real- 83.3%) (Supplementary Table 2). world clinical practice setting During alectinib treatment, the percentage of patients with CNS metastases decreased from 45.2% to The effectiveness of alectinib in real-world clinical 38.7% (Table 4). CNS ORR during alectinib treatment practice was assessed as a secondary endpoint in this was not available for the total number of patients (data study. Response rates, PFS and OS were assessed. collected from a sample of 21 patients are summarized in The mean time from administration of the first dose Supplementary Table 3). In evaluable patients, the ORR of alectinib to the first response was 2.6 months (95% was 28.6% and DCR was 71.4%. The mean duration CI: 2.1–3) (Table 5). Best responses were reported in of response (DOR) was 11 months (95% CI: 2–7) and 110 patients, with an ORR of 54.5% and DCR of 80%. www.oncotarget.com 817 Oncotarget Table 4: Characteristics of the extension of the disease in patients with advanced NSCLC treated previously with crizotinib at diagnosis, during crizotinib, and during alectinib and subsequent treatments Prior to During Subsequent Diagnosis Crizotinib in previous lines alectinib alectinib therapies Patients, n Total 1st line 2nd line 102 104 62 26 99 54 36 TTP (months)   Mean (SD) 12.5 (10.1) 10.6 (7.3) 13.2 (10.9) 10.7 (7.9) 7.8 (6) 4.4 (3.3) −− (10.5–14.5) (8.6–12.7) (9.5–16.8) (6.3–9.3) (3–5.7)   (95% CI) (9.13–12.2)    Median (IQR) 9.4 (4.8–17.8) 9 (4.3–16.9) 8.9 (5.5–20.2) 9 (3.9–16.8) 6.4 (2.6–10.7) 3.7 (1.9–6) −−   (min, max) (0.4–51) (0.4–26.8) (0.7–44) (0.4, 44) (0.3, 27.5) (0.9, 13.8) Type, n (%) 99 (100) 54 (100) 36 (100) 104 (100) 62 (100) 26 (100)   Local recurrence −− 27 (27.3) 15 (27.8) 9 (25) 34 (32.7) 12 (19.4) 9 (34.6)   Regional recurrence −− 13 (13.1) 10 (18.5) 2 (5.6) 13 (12.5) 7 (11.3) 2 (7.7)   Distant recurrence −− 58 (58.6) 29 (53.7) 24 (66.7) 69 (66.3) 43 (69.4) 16 (61.5) Location, n (%)   CNS metastases 25 (24.5) 41 (41.4) 24 (44.4) 13 (36.1) 47 (45.2) 24 (38.7) 4 (15.4)   Liver 17 (16.7) 16 (16.2) 7 (13) 8 (22.2) 23 (22.1) 13 (21) 5 (19.2)   Bone 47 (46.1) 20 (20.2) 11 (20.4) 9 (25) 29 (27.9) 18 (29) 12 (46.2)   Lung 51 (50) 38 (38.4) 23 (42.6) 11 (30.6) 46 (44.2) 30 (48.4) 15 (57.7)   Adrenal gland 0 (0) 3 (3) 3 (5.6) 0 (0) 5 (4.8) 0 (0) 1 (3.8)   Other 38 (37.3) 15 (15.2) 10 (18.5) 5 (13.9) 27 (26) 13 (21) 8 (30.8) A single patient may be classified simultaneously in more than 1 category and report more than 1 tumour location. Not all patients included in the study had data on extension of disease available, thus N may differ from other tables. Abbreviations: CI: confidence interval; CNS: central nervous system; IQR: interquartile range (25–75); min: minimum; max: maximum; SD: standard deviation; TTP: time to progression. The mean time from the first dose of alectinib to the according to previous lines of treatment. Thus, we best response achieved was 4.8 ± 5.1 months (95% CI: classified the effectiveness population into three groups 3.8–5.8). Mean DOR was 7.5 months (95% CI: 5.6–9. 4) of patients: Group 1 (53 patients previously treated with (Table 5). crizotinib only), group 2 (40 patients who had received Following the initiation of alectinib therapy, 70% previous lines of crizotinib and chemotherapy), and group of patients progressed or died during the overall follow- 3 (27 patients who had received prior lines of crizotinib up period. Mean duration of total follow-up for the PFS and other ALK inhibitors, with or without chemotherapy). analysis was 29.9 months (95% CI: 28.3–31.6) and 1-year The analysis of PFS according to previous lines of and 2-year PFS rates were 43.3% and 33.3%, respectively. treatment confirmed that patients included in group 1 Median PFS was 9.4 months (95% CI: 6.3–13.8). Mean reached a median PFS of 7 months (95% CI: 5.5–17), duration of total follow-up for the OS analysis was 29.2 while median PFS was 11.4 months (95% CI: 4.7–17) months (median OS follow-up was 24.1 months [95% for group 2 and 9.5 months (95% CI: 3.4–20) for group CI: 15.6–31.7]). Median OS after total follow-up was 3 (Table 6). The 1-year and 2-year PFS rates were 41.5% 24.1 months (95% CI: 15.6–31.7). The 1-year and 2-year and 35.8%, respectively, for patients in group 1, 50.0% OS rates were 65.8% and 50.8%, respectively. Since the and 32.5%, respectively, for group 2 patients, and 37% diagnosis of advanced NSCLC, 42.4% of patients were and 29.6%, respectively for patients in group 3 (Figure 1). still alive, mean follow-up duration for OS was 59.6 Following the diagnosis of advanced NSCLC, 1-year and months (95% CI: 53.2–66.1) and median OS was 43.3 2-year OS rates were 77.4% and 62.3% for group 1, 90% months (95% CI: 33.4–59.9). The Kaplan-Meier curves and 80% for group 2, and 96.3% and 81.5% for group 3 for PFS and OS after total follow-up are presented in patients, respectively (Figure 2). Figures 1 and 2, respectively. Total follow-up of patients since the initiation of We also performed an exploratory analysis in alectinib found OS rates of 43.4%, 45% and 44.4% for order to obtain a clearer picture of alectinib effectiveness groups 1, 2 and 3, respectively. www.oncotarget.com 818 Oncotarget Table 5: First and best responses achieved during alectinib treatment First response, n (%) Patients 111 (100)    Complete response (CR) 2 (1.8)    Partial response (PR) 55 (49.5)    Stable disease (SD) 29 (26.1)    Progressive disease (PD) 15 (13.5)    Not evaluable (NE) 10 (9) Time to first response (months) Valid N (107)    Mean (SD; 95% CI) 2.6 (2.1; 2.1–3)    Median (IQR; min, max) 2.4 (1.5–3; 0, 14.6) Best response, n (%) 110 (100)    Complete response (CR) 5 (4.5)    Partial response (PR) 55 (50)    Stable disease (SD) 28 (25.5)    Progressive disease (PD) 14 (12.7)   Not evaluable 8 (7.3) Objective response rate (ORR), n (%) 110 (100)    CR + PR 60 (54.5) Disease control rate (DCR), n (%) 110 (100)    CR + PR + SD 88 (80) Time to best response (months) Valid N (106)    Mean (SD; 95% CI) 4.8 (5.1; 3.8–5.8)    Median (IQR; Min, max)) 2.8 (1.9–5.9; 0.1, 21.2) Duration of response (DOR, months) Valid N (37)    Mean (SD; 95% CI) 7.5 (5.8; 5.6–9.4)    Median (IQR; min, max) 5.3 (3.4–9.2; 0.2, 22.4) Abbreviations: CI: confidence interval; IQR: interquartile range (25–75); min: minimum; max: maximum; SD: standard deviation. Figure 1: Kaplan-Meier curve for progression-free survival after total follow-up of ALK+ NSCLC patients treated with alectinib. Progression free survival (PFS) was analyzed after total follow-up (FUP) according to prior lines of treatment in the overall population (left panel) and in each subgroup of the effectiveness population (right panel): Group 1 (53 patients previously treated with crizotinib only), group 2 (40 patients who had received previous lines of crizotinib and chemotherapy), and group 3 (27 patients who had received prior lines of crizotinib and other ALK inhibitors, with or without chemotherapy). www.oncotarget.com 819 Oncotarget Table 6: Type, severity and management of AEs reported during alectinib treatment Total Grade <3 Grade ≥3 Patients with AEs, n (%) 43 (35.8) 18 (15) 17 (14.2) Reported AEs, n (%) 70 (100) 27 (38.6) 22 (31.4)    Serious AEs 23 (32.9) 4 (14.8) 10 (45.5)    AEs related to alectinib 33 (47.1) 17 (63) 7 (31.8)   Not evaluable 8 (11.4) 3 (11.1) 1 (4.5) Action taken, n (%)    No action taken 19 (27.1) 3 (11.1) 7 (31.8)    Study drug delayed 2 (2.9) 0 (0.0) 2 (9.1)    Study drug withheld temporarily 18 (25.7) 13 (48.1) 3 (13.6)   Dose reduction 30 (42.9) 16 (59.3) 5 (22.7)    Study drug interrupted permanently 4 (5.7) 0 (0.0) 4 (18.2) Abbreviations: CI: confidence interval; IQR: interquartile range (25–75); SD: standard deviation. A total of 43 patients (35.8%) reported 70 AEs bilirubin levels (2.5%), myalgia/myositis (2.5%) and during the treatment with alectinib. Grade ≥3 AEs were vomiting (1.7%). reported by 14.2% of patients (Table 6). A total of 33 AEs (47.1%) were related to alectinib treatment (63.0% of DISCUSSION grade <3 AEs and 31.8% of grade ≥3 AEs). Dose reduction was applied for 42.9% of AEs while only 5.7% of total The availability of next-generation ALK inhibitors AEs led to permanent discontinuation. Most patients has widened the therapeutic landscape for ALK+ NSCLC (75.5%) achieved total recovery. patients. However, further information on real-world Classification and proportion of AEs according to treatment patterns is still needed in this context, as some MedDRA are provided in Supplementary Table 4. The patient subpopulations are underrepresented in clinical most frequent AEs were increased transaminase levels studies. This study gathered information from patients (5.8%, including ALT, AST, GTT and others), dyspnea with advanced ALK+ NSCLC treated in 38 healthcare (4.2%), asthenia (2.5%), fatigue (2.5%), increased serum centers, who were included in an EAP of alectinib after Figure 2: Kaplan-Meier curve for overall survival after total follow-up of ALK+ NSCLC patients treated with alectinib. Overall survival (OS) was analyzed after total follow-up (FUP) according to prior lines of treatment in the overall population (left panel) and in each subgroup of the effectiveness population (right panel): Group 1 (53 patients previously treated with crizotinib only), group 2 (40 patients who had received previous lines of crizotinib and chemotherapy), and group 3 (27 patients who had received prior lines of crizotinib and other ALK inhibitors, with or without chemotherapy). www.oncotarget.com 820 Oncotarget progression on crizotinib, among other prior therapies. lorlatinib [41] were designed to overcome resistance to Current clinical guidelines recommend the use of next- first- and even second-generation ALK-inhibitors [7, 8]. generation TKIs (in particular, alectinib) as first-line In our study, patients who followed subsequent lines of therapy for advanced ALK+ NSCLC. Our aim was therapy after alectinib treatment were mostly prescribed to provide a complete clinical characterization of an lorlatinib (65.2% of 46 patients) followed by brigatinib ALK+ NSCLC population of patients included in these (32.6%). Non-targeted therapies such as chemotherapy types of access programs, and to assess the outcomes of were prescribed to 28.3% of patients, while 10.9% advanced ALK+ NSCLC patients under sequential lines of patients were treated with immunotherapy. These of treatment. Although available information was not changes in treatment patterns reflect the emergence complete in some cases, we observed some interesting of new therapeutic alternatives and the update to trends in real-world clinical practice from these analyses. recommendations in clinical guidelines that occurred The baseline characteristics of the study patient between the initial NSCLC diagnosis and the termination population were consistent with those reported in lung of the study. cancer patients with ALK-rearranged tumors, who are The use of sequential lines of active therapies often younger than the general lung cancer population and resulted in an increase in the percentage of patients with present light or non-smoking habits and adenocarcinoma ECOG PS 0 and 1 (from 26% to 38% at baseline, to 38% histology [26]. Our patient sample had similar features to 53%, respectively). Alectinib treatment, which was to other ALK+ NSCLC populations included in several mostly initiated after disease progression, was still able to real-world studies [27–32]: half the patients were female, provide patients with optimal performance status at similar with a mean age below 60 years, most were non-smokers, rates (33% and 42%, respectively), which translated into and they presented stage IV disease and adenocarcinoma patients’ perception of being able to perform regular histology. ECOG PS 0 and 1 were recorded in a high activities with no difficulties. Alectinib treatment achieved percentage of patients and 20.8% presented brain partial response in half of patients, with an ORR of 54.5% metastases at diagnosis. All patients included in this study and DCR of 80%. Following the initiation of alectinib, the had received crizotinib in a treatment line prior to alectinib total median OS (24.1 months; 95% CI: 15.6–31.7) and (mostly in the first and second line). The most common median PFS (9.4 months; 95% CI: 6.3–13.8) were found type of non-targeted therapy received prior to alectinib to be in the same range as the outcomes reported in the was chemotherapy (45.8% of patients), while ceritinib and alectinib phase II trials (NP28761 and NP28673) and in brigatinib were used to a lesser extent. Immunotherapy the phase III ALUR trial in patients who were intolerant was used in the first, second and third line of treatment, or progressed on crizotinib [9, 12]. Our OS data improve but only in a very small proportion of patients (included on the previously reported results of a French EAP of in 1.7% of patients who may also have received other crizotinib for ALK+ NSCLC patients, who achieved a targeted therapies). This low frequency of prescription median OS of 16.6 months after initiation of crizotinib. of immunotherapy could be explained by the poor and This superiority of alectinib versus crizotinib in EAP is limited evidence of efficacy of immunotherapy in the consistent with the reported superiority of alectinib versus treatment of ALK+ NSCLC patients [33–35]. The median crizotinib when used as first-line treatment in naïve ALK+ duration of previous lines of treatment was 9.6 months, in NSCLC patients [17, 42]. the range of the DOT with some agents such as crizotinib, In our real-world study, the median OS following as reported in registrational trials [5]. the diagnosis of advanced ALK+ NSCLC was 43.3 With the approval of new second- and third- months (95% CI: 33.4–59.9) considering that all patients generation ALK inhibitors (alectinib, brigatinib and had received crizotinib prior to alectinib and more than lorlatinib, among others), the therapeutic options for first 40% of patients had received chemotherapy prior to ALK- and subsequent lines of treatment were expanded, offering directed therapy. The updated data from the ALEX trial clinicians a wider repertoire of therapeutic agents for on alectinib in the first-line setting confirmed a 5-year OS initial treatment and the possibility of choosing between rate of 62.5% (95% CI 54.3–70.8) with alectinib versus different treatment sequences for advanced ALK+ NSCLC 45.5% (95% CI 33.6–57.4) with crizotinib (OS was not [22, 36–38]. Current treatment guidelines recommend the reached with alectinib versus 57.4 months with crizotinib; use of multiple ALK inhibitors in the advanced setting [24, stratified HR 0.67, 95% CI: 0.46–0.98). Although a higher 39]. In clinical practice, next-generation ALK inhibitors 2-year OS rate of 72.5% was reported in the alectinib (alectinib, ceritinib and brigatinib) have generally arm compared to our recorded 2-year OS of 50.8%, all replaced the first-generation TKI crizotinib as first-line these data support the efficacy of next-generation ALK treatment. This has been possible due to the improved inhibitors in front-line therapy [17]. pharmacological properties of next-generation versus In this paper, we have described the efficacy of first-generation ALK TKIs, which include greater potency/ alectinib in terms of PFS or OS between patients grouped selectivity, CNS penetration and targeting of resistant according to the number and type of previous treatments mutations [40, 41]. Third-generation inhibitors such as since initiation of alectinib. In this regard, the small www.oncotarget.com 821 Oncotarget sample size and intra-group heterogeneity should be taken Our study has some limitations. First, the limited into consideration. Moreover, the treatment sequences sample size did not allow us to obtain statistical described herein are not representative of the current ALK significance in the subgroup analyses. However, and treatment landscape due the subsequent incorporation of despite the limited number of patients, the absence of new generation ALK inhibitors. Identification of the most very stringent inclusion criteria makes our results more suitable subsequent lines of treatment for ALK+ NSCLC representative of a real-world setting, and reflect the patients is critical in the therapeutic decision-making heterogeneity of the population with ALK+ NSCLC. The process. However, the optimal sequence of ALK inhibitors limitation inherent to the analysis of data extracted from is still under consideration. clinical practice documentation must also be taken into We were also able to observe a benefit of alectinib account, as medical information recorded for reasons treatment in terms of CNS activity after several prior other than research can be incomplete, and some data were lines of therapy. CNS metastases were detected after probably lost during patient follow-up. It is important to first-line crizotinib therapy in 44.4% of patients. This highlight that most patients were polymedicated and, is consistent with the reported data on progression of therefore, some results should be interpreted with caution. preexisting intracranial lesions or the development of new In conclusion, the results obtained in alectinib ones while patients were under crizotinib treatment, as a clinical trials in patients with ALK+ NSCLC can be common manifestation of acquired resistance [5, 43]. In observed in a less selective patient population treated our study, the overall percentage of patients with CNS during routine clinical practice, even in patients who had metastases fell to 38.7% after the initiation of alectinib been previously treated with several lines of therapy. The treatment, irrespective of prior treatment lines. Alectinib median OS achieved since diagnosis of advanced disease showed a DCR of 71.4% and a median DOR of 10.2 in patients treated with next-generation ALK inhibitors months, which is in line with the superior CNS activity (such as alectinib) after crizotinib failure highlights the and significantly delayed CNS progression reported in importance of early accurate diagnosis and access to next- clinical trials [13, 14]. It is also worth noting that over generation agents for targeted therapy in molecularly- 50% of patients received WBRT to treat CNS metastases defined patient populations. The results of our study at diagnosis and before alectinib treatment, which could provide details on real-world treatment patterns when new potentially lead to chronic toxicity. The choice of alectinib ALK inhibitors are incorporated into the drug repertoire as a front-line treatment in this setting could reduce the for ALK+ NSCLC patients, and provide initial information need for WBRT, and therefore the accumulated toxicity, on the use of sequential ALK therapies. Further studies are whilst not compromising efficacy. It is interesting to note warranted to determine the optimal sequence of treatments that among symptomatic patients with CNS metastases, for ALK-rearranged NSCLC in terms of prolonging only 5 out of 23 patients were treated with corticosteroids survival. before initiating alectinib treatment. This may be based on the high expectations regarding alectinib efficacy MATERIALS AND METHODS in the management of ALK+ NSCLC-associated CNS metastases according to the available evidence [44]. Patients In our study, no restrictions were established regarding comorbidities, concomitant medications, number Patients from 38 healthcare institutions, diagnosed or type of previous treatment lines or the different clinical with advanced/metastatic ALK+ NSCLC, aged ≥18 years approaches selected to treat ALK+ NSCLC patients at who were treated with alectinib through an expanded the time of recruitment. Our real-world data confirm that access program (EAP) between April 1, 2017 and March alectinib was well tolerated in this unselected patient 31, 2018, were enrolled in this study. All patients had population. In this context, crizotinib-led sequences progressed on crizotinib, which was a mandatory criterion and the use of chemotherapy were the most common to be included in the study, as this was the first approved prior treatments. In terms of subsequent treatments after indication for the use of alectinib by the European the alectinib regimen, lorlatinib and brigatinib were Medicine Agency (EMA. A total of 128 patients were the preferred therapies. Our findings seem to support selected. Patients with any medical or psychological the feasibility of the sequential use of ALK inhibitors condition that, in the physician’s opinion, might and the additional and clinically meaningful benefits of compromise the ability of the patient to give informed incorporating next-generation ALK inhibitors into the consent, were excluded. The final number of assessable therapeutic armamentarium. More interestingly, our study patients meeting selection criteria was 120. reflects the real dynamic and changing patterns of treatment in a Spanish population of ALK+ NSCLC patients during Study design routine clinical practice, and suggests good adherence of clinicians to the most up-to-date recommendations included This was a multicenter, retrospective patient chart in clinical guidelines and emerging therapeutic choices. review of observational (non-interventional) nature www.oncotarget.com 822 Oncotarget which aimed to characterize the clinical practice patterns association analyses between quantitative variables with in the management of advanced ALK+ NSCLC patients normal distribution, the two-sided t-test was used, while included within the EAP, as well as to describe the main the Mann-Whitney U test was used for the remaining patient outcomes. Available data from Case Report variables. Fisher’s test or the Chi-square test was used to Forms (CRFs) were collected between November 2019 determine the association between qualitative variables. and November 2020, when the database was locked. A p-value < 0.05 was considered statistically significant Only data registered before the initiation of the study unless otherwise specified. The statistical analysis was (the first Ethics Committee approval was obtained performed using SAS software package, version 9.4. on June 26, 2019) were extracted, thus reflecting the routine management and regimen patterns used to treat Abbreviations the disease and avoiding interference with physicians’ clinical practice. Patients had to sign informed consent. AE: adverse events; ALK+ NSCLC: advanced To comply with the retrospective nature of the study, the anaplastic lymphoma kinase (ALK)-positive non-small- Ethics Committee authorized data collection for patients cell lung cancer; ALT: alanine transaminase; AST: who had died or had been lost to follow-up at the time of aspartate transaminase; CNS: central nervous system; study initiation. The study was conducted in the medical CT: computed axial tomography; HR: hazard ratio; DCR: oncology departments at 38 Spanish sites, seeking a disease control rate; DOR: duration of response; DOT: homogeneous geographical distribution. Its multicenter duration of treatment; ECOG PS: Eastern Cooperative nature aimed to improve the representativeness of the Oncology Group performance status; GGT: gamma- study population in Spain. glutamyl transferase; IQR: interquartile range; MRI: magnetic resonance imaging; ORR: objective response Study endpoints rate; OS: overall survival; PFS: progression-free survival; TKI: tyrosine kinase inhibitor. The demographic and clinical profile of ALK+ NSCLC patients within the EAP who received alectinib Author contributions on crizotinib failure were determined as primary objectives. The clinical and demographic variables R. B-C., J.d.C., P. G., R. G-C., R G. and M. C. were collected at diagnosis, at inclusion in the EAP and participated in the conception, design, follow-up and initiation of alectinib treatment, and during subsequent analysis of the study. All the authors contributed to the regimens. Effectiveness of alectinib and management of research, development and content of the manuscript as metastases were assessed as secondary endpoints. Best well as reviewed and approved the final draft. response rates were defined by the response evaluation criteria in solid tumors (RECIST). Progression free survival (PFS) and overall survival (OS) were assessed ACKNOWLEDGMENTS at 1 and 2 years since initiation of alectinib treatment as well as overall median PFS/OS since the initiation of The authors would like to thank Dr. Susana alectinib treatment to disease progression or death. Data Cañón-Sánchez from Medical Statistics Consulting S.L. on the diagnostic techniques used for CNS detection (Valencia) for providing scientific support and medical and characterization and type of local treatments used writing services. for metastases management were collected. Safety and tolerability of treatments were recorded throughout the Ethical disclosure study, and adverse events (AEs) were graded according to the National Cancer Institute´s Common Terminology Patient medical information obtained for this study Criteria for Adverse Events. was confidential and could only be disclosed to third parties as provided in the informed consent form signed Statistical analyses by the patients, unless permitted or required by law. Roche Farma S.A. maintains confidentiality standards by coding Categorical variables were expressed as numbers each patient enrolled in this study through assignment of a and percentages, and continuous variables as mean and unique subject identification number. standard deviation (SD), or as medians and interquartile ranges (IQR) for variables without normal distribution. CONFLICTS OF INTEREST Distributions of PFS and OS were estimated using the Kaplan-Meier method. The Log-rank test was used for R. B.-C. reports advisory honoraria from Roche, comparing the survival distribution of 2 or more groups. Bristol-Myers Squibb, and AstraZeneca; speaker honoraria Normal distribution of the quantitative variables was tested from Roche, Bristol-Myers Squibb, and Amgen; and using the Kolmogorov-Smirnov statistical test. For the grants from Roche. www.oncotarget.com 823 Oncotarget P. G. reports consultancy fees from Abbvie, Amgen, J. d. C. reports educational fees from Astra Zeneca, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol- Bristol-Myers Squibb, Merck-Sharp-Dome, and Roche; Myers Squibb, GlaxoSmithKline, Janssen, Lilly, Merck- consultancy fees from AstraZeneca, Bayer, Boehringer Sharp-Dome, Medscape, Novartis, Pfizer, Roche, Takeda Ingelheim, Bristol-Myers Squibb, GlaxoSmithKline, and Sanofi, and speaker honoraria from AstraZeneca, Janssen-Cilag, Lilly, Merck-Sharp-Dome, Novartis, Pfizer, Boehringer Ingelheim, Bristol-Myers Squibb, Janssen, Roche, and Takeda.​ Merck-Sharp-Dome, Novartis, Pfizer, Roche, and Takeda. All potential conflicts of interests were outside of R. G.-C. reports consultancy fees and speaker the submitted work. honoraria from Merck-Sharp-Dome, Bristol-Myers, Roche, Boehringer Ingelheim, Pfizer, Novartis, FUNDING AstraZeneca, Lilly, Takeda, Bayer and Janssen. R. P. reports speaker honoraria from Guardant This study was sponsored and financed by Roche Health, Pfizer, Roche, Boehringer-Ingelheim, Eli-Lilly, Farma, S.A. Bristol-Myers Squibb, AstraZeneca, and Merck-Sharp- Dome; travel/meeting attendance expenses from Merck- Sharp-Dome and Roche, and membership of data safety REFERENCES monitoring from Boehringer-Ingelheim and Roche. 1. Soda M, Choi YL, Enomoto M, Takada S, Yamashita A. A. reports consultancy fees from Roche, Takeda, Y, Ishikawa S, Fujiwara S, Watanabe H, Kurashina AstraZeneca, and Bristol-Myers Squibb. K, Hatanaka H, Bando M, Ohno S, Ishikawa Y, et al. C. B. reports consultancy fees from Boehringer- Identification of the transforming EML4-ALK fusion gene Ingelheim and AstraZeneca; speaker honoraria from in non-small-cell lung cancer. Nature. 2007; 448:561–66. Pfizer, Merk, Roche, Bristol-Myers Squibb, Takeda, https://doi.org/10.1038/nature05945. 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