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Brain Penetration of Lorlatinib: Cumulative Incidences of CNS and Non-CNS Progression with Lorlatinib in Patients with Previously Treated ALK-Positive Non-Small-Cell Lung Cancer

Brain Penetration of Lorlatinib: Cumulative Incidences of CNS and Non-CNS Progression with... Background Lorlatinib is a potent, third-generation ALK/ROS1 tyrosine kinase inhibitor (TKI) designed to penetrate the blood–brain barrier. Objective We report the cumulative incidence of central nervous system (CNS) and non-CNS progression with lorlatinib in patients with ALK-positive non-small-cell lung cancer (NSCLC) previously treated with ALK TKIs. Patients and methods In an ongoing phase II study (NCT01970865), 198 patients with ALK-positive NSCLC with ≥ 1 prior ALK TKI were enrolled into expansion cohorts (EXP) based on treatment history. Patients received lorlatinib 100 mg once daily. Patients were analyzed for progressive disease, categorized as CNS or non-CNS progression, by independent central review. Cumulative incidence probabilities were calculated adopting a competing risks approach. Results Fifty-nine patients received crizotinib as their only prior ALK TKI (EXP2–3A); cumulative incidence rates (CIRs) of CNS and non-CNS progression were both 22% at 12 months in patients with baseline CNS metastases (n = 37), and CIR of non-CNS progression at 12 months was higher versus that for CNS progression in patients without baseline CNS metas- tases [43% vs. 9% (n = 22)]. In patients who received ≥ 1 prior second-generation ALK TKI [EXP3B–5 (n = 139)], CIR of non-CNS progression at 12 months was higher versus that for CNS progression in patients both with and without baseline CNS metastases (35% vs. 23% (n = 94) and 55% vs. 12% (n = 45), respectively). Conclusions Lorlatinib showed substantial intracranial activity in patients with pretreated ALK-positive NSCLC, with or without baseline CNS metastases, whose disease progressed on crizotinib or second-generation ALK TKIs. ClinicalTrials.gov identifier NCT01970865. Key Points Prior presentation Some of the results from these analyses have been presented at the International Association for the Study of Lung Cancer (IASLC) 19th World Conference on Lung Cancer Lorlatinib is a potent, brain-penetrant, third-generation (WCLC), 23–26 September 2018; Toronto, Ontario, Canada; ALK/ROS1 TKI. American Society of Clinical Oncology (ASCO) meeting 1–5 June 2018, Chicago, Illinois, USA, and European Medical Society We performed an analysis of CNS and non-CNS pro- for Oncology (ESMO) meeting, 27 September–1 October 2019, gression in patients with pretreated ALK+ NSCLC. Barcelona, Spain. Our results indicate that lorlatinib is active in the treat- Electronic supplementary material The online version of this ment and prevention of CNS metastases in patients with article (https ://doi.org/10.1007/s1152 3-020-00702 -4) contains ALK+ NSCLC, including those who had progressed on supplementary material, which is available to authorized users. crizotinib or second-generation TKIs. * Todd M. Bauer tbauer@tnonc.com Vall d’Hebron University Hospital, Vall d’Hebron Institute of Oncology (VHIO), Passeig de la Vall d’Hebron, 119-129, Sarah Cannon Cancer Research Institute/Tennessee 08035 Barcelona, Spain Oncology, PLLC, 250 25th Ave N, Nashville, TN 37203, Pfizer Oncology, 10777 Science Center Dr, La Jolla, CA, USA USA Pfizer Oncology, Via Anna Maria Mozzoni, 12, Milan, Italy Massachusetts General Hospital, 55 Fruit St, Boston, MA 02114, USA Pfizer Oncology, 280 Shennecossett Rd, Groton, CT, USA Vol.:(0123456789) 56 T. M. Bauer et al. non-CNS progression in patients with ALK-positive NSCLC 1 Introduction previously treated with ALK TKIs from the phase II portion of the phase I/II study. We also present antitumor activity Central nervous system (CNS) metastases are a known data in previously irradiated brain lesions with progression complication of anaplastic lymphoma kinase (ALK)-pos- at baseline and in patients with leptomeningeal disease. itive non-small-cell lung cancer (NSCLC), occurring in approximately 30% of patients at the time of diagnosis [1]. In general, the presence of CNS metastases is associated 2 Materials and Methods with a poor prognosis, including decreased progression-free survival, and can lead to neurocognitive dysfunction that can 2.1 Study Design and Participants negatively affect patient quality of life [2 –4]. ALK tyrosine kinase inhibitors (TKIs), including the The full methodology for this ongoing, open-label, single- first-generation TKI crizotinib [5 ] and second-generation arm, multicenter phase II trial has been published [18]. ALK TKIs [6–8], are standard therapies for patients with Eligible patients were aged ≥ 18 years and had histologi- ALK-positive NSCLC. However, most patients treated with cally or cytologically confirmed metastatic NSCLC with crizotinib will relapse over time because of the development either ALK or ROS1 rearrangement. ALK positivity was of resistance and poor intracranial disease control [9–11]. determined locally on the basis of the US Food and Drug The CNS is a common site of progression with crizotinib, Administration-approved fluorescence in  situ hybridiza- likely because of poor CNS penetration as a result of P-gly- tion assay (Abbott Molecular, Abbott Park, IL, USA) or by coprotein-mediated efflux across the blood–brain barrier immunohistochemistry (Ventana Medical Systems, Tucson, (BBB) [12]. Despite the development of more potent and AZ, USA). An Eastern Cooperative Oncology Group per- BBB-permeable second-generation ALK TKIs, the emer- formance status of ≤ 2 and ≥ 1 measurable target extrac- gence of resistance and progression of CNS metastases ranial lesion according to Response Evaluation Criteria in remain clinically significant issues in the management of Solid Tumors (RECIST), version 1.1, were also required. ALK-positive NSCLC. Patients with untreated or treated (including those con- Lorlatinib was specifically designed to penetrate the BBB trolled with stable or decreasing steroid use within the last and is a highly potent, selective, third-generation macrocy- 2 weeks) asymptomatic CNS metastases were permitted. clic inhibitor of ALK and ROS1 with broad ALK mutational CNS metastases may be newly diagnosed or be present as coverage [13]. Using radiolabeling and positron emission progressive disease after surgery, whole-brain radiotherapy, tomography imaging, lorlatinib demonstrated high BBB or stereotactic radiosurgery. Prior radiotherapy must have permeability and rapid brain uptake in animals [14, 15]. been completed within 2 weeks of study entry (whole-brain Lorlatinib has also shown antitumor activity in ALK-posi- radiotherapy: ≤ 4 weeks). Patients with leptomeningeal dis- tive intracranial tumor models [16]. The high CNS penetra- ease/carcinomatosis were allowed to enroll if the disease tion of lorlatinib noted in preclinical studies was confirmed was visualized on magnetic resonance imaging (MRI) or if in the clinic where the mean ratio of cerebrospinal fluid baseline CSF-positive cytology was available. (CSF)/plasma (unbound) was 0.75 in four patients, who had Patients were enrolled into expansion cohorts (EXP) by matched samples available, from the phase I portion of the their ALK (EXP1–5) or ROS1 (EXP6) status and treatment ongoing phase I/II study (NCT01970865) [17]. This phase history. In this analysis, we focused on previously treated I/II study demonstrated robust overall and intracranial anti- ALK-positive patients who were enrolled into EXP2–5. tumor activity of lorlatinib in patients with ALK-positive Specific enrolment criteria for these ALK-positive cohorts NSCLC, most of whom had CNS metastases at baseline were as follows: progression following previous crizotinib and experienced treatment failure with ≥ 1 ALK TKI [17, only (EXP2), progression following previous crizotinib and 18]. On the basis of data from this phase I/II study, the US one or two regimens of chemotherapy given before or after Food and Drug Administration granted lorlatinib acceler- crizotinib (EXP3A), progression following one previous ated approval status in November 2018 for the treatment second-generation ALK TKI with or without chemotherapy of patients with ALK-positive metastatic NSCLC who had (EXP3B), and ALK-positive patients with disease progres- disease progression on crizotinib and ≥ 1 other ALK TKI sion following two (EXP4) or three (EXP5) previous ALK or who had disease progression on alectinib or ceritinib as TKIs with or without chemotherapy. the first ALK TKI received. In May 2019, the European Patients were administered lorlatinib orally at a dose of Commission also approved lorlatinib for use in these patient 100 mg once daily until progression, unacceptable toxicity, populations. death, or withdrawal. Treatment beyond progression was To further assess the effect of brain penetration with permitted if the patient was still experiencing clinical benefit lorlatinib in the clinic, we report an analysis of CNS and per the investigator’s discretion. CIRs of CNS and Non-CNS Progression with Lorlatinib in ALK-Positive NSCLC 57 All patients provided written, informed consent before Other efficacy and statistical methodology has been previ- participation. The institutional review board or independ- ously described [18]. The data cutoff for this analysis was ent ethics committee at each participating site approved 2 February 2018. the protocol, which complied with the International Ethi- cal Guidelines for Biomedical Research Involving Human Subjects, Good Clinical Practice guidelines, the Declaration of Helsinki, and local laws.3 Results 2.2 Assessments3.1 Patients All patients underwent baseline tumor imaging by computed Patients were enrolled between 15 September 2015, and 3 tomography and brain imaging by MRI. Computed tomog- October 2016. Baseline characteristics of the overall phase raphy and MRI scans were to be taken every 6 weeks for the II population (EXP1–6) have been previously reported first 30 months and then every 12 weeks thereafter until pro- [18]. In this analysis, we report data from the 198 patients gressive disease or the start of a new anticancer treatment. with ALK-positive NSCLC who had received ≥ 1 ALK Response was assessed according to modified RECIST, ver - TKI and received ≥ 1 dose of lorlatinib (EXP2–5). Of these sion 1.1, which allowed for up to five CNS target lesions, patients, 59 received crizotinib as their only prior ALK as assessed by independent central radiology review (ICR). TKI (EXP2–3A) and 139 received ≥ 1 prior second-gen- Adverse events (AEs) associated with the CNS were ana- eration ALK TKI (EXP3B–5). Baseline CNS metastases lyzed. They consisted of preferred terms from the Medical (measurable/non-measurable) were present in 37 patients Dictionary for Regulatory Activities System Organ Class (62.7%) from EXP2–3A and in 94 patients (67.6%) from (SOC) of psychiatric disorders and SOC of nervous system EXP3B–5. Baseline characteristics of the subgroups ana- disorders. Peripheral neuropathy was excluded as it repre- lyzed are shown in Table 1 and were generally comparable. sented an AE associated with the peripheral nervous sys- There were more Asian patients (51.1%) and fewer White tem, but not the CNS. These AEs were assessed at baseline, patients (33.3%) in the EXP3B–5 subgroup without base- every subsequent visit, and ≥ 28 days after the final lorlatinib line CNS metastases compared with all other subgroups administration, and were graded according to the National (27.0–31.8% and 50.0–54.3%, respectively). Among Cancer Institute Common Terminology Criteria for Adverse patients with baseline CNS metastases in EXP2–3A and Events, version 4.03. EXP3B–5, respectively, eight (21.6%) and 30 (31.9%) had irradiated brain lesions with progression at baseline; 2.3 Statistical Analysis the median number was 3.5 lesions (range 2–10) and 5.0 lesions (range 1–11) per patient. At the time of data cut- Patients were analyzed for progressive disease events, cat- off, the median duration of follow-up for progression-free egorized as either CNS or non-CNS progression, by ICR. survival for EXP2–3A and EXP3B–5 was 18.2  months Any new CNS lesions or progression of pre-existing CNS (95% confidence interval (CI) 18.0–21.1 months) and 19.1 lesions versus baseline was considered a CNS progres- months (95% CI 16.5–20.8 months), respectively. sion, while any new lesion or progression of pre-existing lesions in areas outside the CNS was considered non-CNS 3.2 CNS Versus Non‑CNS Progression progression. If both CNS and non-CNS progression were presented simultaneously as the first progressive event, Figure  1 shows the cumulative incidences for CNS pro- patients were considered to have CNS progression as their gression, non-CNS progression, and death with lorlatinib first event. The probability of a first event being a CNS pro- in patients who had received prior crizotinib as their only gression, non-CNS progression, or death was estimated by ALK TKI (EXP2–3A). In patients with baseline CNS metas- cumulative incidences using a competing risks approach in tases (n = 37), the cumulative incidence rates (CIRs) of CNS patients with or without baseline CNS metastases. EXP2 and non-CNS progression were 16% and 11% at 6 months, and EXP3A were pooled because the included patients had respectively, and 22% and 22% at 12 months, respectively all been treated with crizotinib (first-generation ALK TKI) (Fig. 1a; Table 2). In patients without baseline CNS metas- as their only prior ALK TKI. EXP3B, EXP4, and EXP5 tases (n = 22), the CIR of non-CNS progression was higher were pooled because the included patients had all received versus that for CNS progression at both 6 months (24% vs. ≥ 1 prior second-generation ALK TKI. 9%) and 12 months (43% vs. 9%; Fig. 1b and Table 2). In an unplanned subgroup analysis, intracranial In patients who had received ≥ 1 prior second-gener- response was derived based on irradiated brain lesions ation ALK TKI (EXP3B–5) with baseline CNS metasta- with progression at baseline and new brain lesions only. ses (n = 94), the CIR of non-CNS progression was higher 58 T. M. Bauer et al. Table 1 Baseline characteristics of the pooled subgroups for this analysis by baseline metastases a a CharacteristicPrior crizotinib (EXP2–3A; n = 59) At least one prior second-generation ALK TKI (EXP3B–5; n = 139) Baseline CNS metastases No baseline CNS metastases Baseline CNS metastases No baseline b b (n = 37) (n = 22) (n = 94) CNS metastases (n = 45) Age, years  Median 54.0 58.0 50.5 56.0  Range 30–74 37–85 29–77 33–83 Sex, n (%)  Male 12 (32.4) 8 (36.4) 40 (42.6) 21 (46.7)  Female 25 (67.6) 14 (63.6) 54 (57.4) 24 (53.3) Race, n (%)  White 20 (54.1) 11 (50.0) 51 (54.3) 15 (33.3)  Asian 10 (27.0) 7 (31.8) 30 (31.9) 23 (51.1)  Black 0 0 0 1 (2.2)  Other 1 (2.7) 1 (4.5) 4 (4.3) 2 (4.4)  Not specified 6 (16.2) 3 (13.6) 9 (9.6) 4 (8.9) ECOG PS, n (%)  0 17 (45.9) 11 (50.0) 45 (47.9) 16 (35.6)  1 20 (54.1) 10 (45.5) 44 (46.8) 28 (62.2)  2 0 1 (4.5) 5 (5.3) 1 (2.2) Irradiated brain lesions with progression at screening  n (%) 8 (21.6) 30 (31.9)  Number of lesions,   Median 3.5 5.0   Range 2–10 1–11 ALK anaplastic lymphoma kinase, CNS central nervous system, ECOG PS Eastern Cooperative Oncology Group performance status, EXP expansion cohort, TKI tyrosine kinase inhibitor With or without chemotherapy Includes patients with measurable and/or non-measurable CNS lesions Number of patients with irradiated brain lesions with progression at screening by independent central review versus that for CNS progression at 6  months (25% vs. metastases at 6 months (27% vs. 15% and 38% vs. 11%, 14%) and at 12 months (35% vs. 23%; Fig. 2a; Table 2). respectively) and at 12 months (37% vs. 23% and 53% vs. Patients without baseline CNS metastases (n = 45) also had 11%, respectively; Supplementary Table A.1). a higher CIR of non-CNS progression versus that for CNS progression, with CIRs of 37% versus 12% at 6 months and 3.3 Intracranial Antitumor Activity 55% versus 12% at 12 months (Fig. 2b; Table 2). Of all patients previously treated with ≥ 1 prior second- Baseline measurable CNS metastases were present in 24 generation ALK TKI, 121 of 139 received a second-gen- (64.9%) out of 37 patients in EXP2–3A and 57 (60.6%) eration ALK TKI as their last ALK TKI prior to receiving out of 94 patients in EXP3B–5. In EXP2–3A, intracranial lorlatinib, with most having last received alectinib (n = 62) responses were observed in 21 (87.5%, 95% CI 67.6–97.3) or ceritinib (n = 47). The curves of cumulative incidence of 24 patients (Table 3). Median duration of response was for CNS and non-CNS progression were similar to those not reached (95% CI 15.2 months–not estimable). Of the for the overall EXP3B–5 subgroups (Fig. 3). Similarly, the 57 patients in EXP3B–5, 31 (54.4%; 95% CI 40.7–67.6) CIR of non-CNS progression was higher versus that for achieved an intracranial response and the median duration CNS progression in patients with or without baseline CNS of response was 12.4 months (95% CI 5.8–not estimable). CIRs of CNS and Non-CNS Progression with Lorlatinib in ALK-Positive NSCLC 59 Fig. 1 Cumulative incidence 1.0 of CNS progression, non-CNS CNS PD 0.9 progression, and death with lor- Non-CNS PD latinib in patients with prior cri- 0.8 zotinib* (EXP2–3A). a Patients Death 0.7 with baseline CNS metastases and b patients without baseline 0.6 CNS metastases. *With or with- 0.5 out chemotherapy. CNS central 0.4 nervous system, EXP expansion cohort, PD progressive disease 0.3 0.2 0.1 0.0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 Time (months) Cumulative no. of events CNS PD 00233368888888 8 8 Non-CNS PD 00001244455789 10 10 Death 0001111111111 11 1 1.0 0.9 CNS PD 0.8 Non-CNS PD 0.7 Death 0.6 0.5 0.4 0.3 0.2 0.1 0.0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 Time (months) Cumulative no. of events CNS PD 00222222222222 2 2 001114555699 9101 10 0 Non-CNS PD Death 00 111 11 11 11 11 11 1 Table 2 Cumulative incidence probabilities for CNS progression, non-CNS progression, and death at 6 and 12 months a a Prior crizotinib (EXP2–3A; n = 59) At least one prior second-generation ALK TKI (EXP3B–5; n = 139) Baseline CNS metastases No baseline CNS metastases Baseline CNS metastases No baseline CNS (n = 37) (n = 22) (n = 94) metastases (n = 45) CNS progression  6 months 0.16 (0.07–0.30) 0.09 (0.02–0.25) 0.14 (0.07–0.22) 0.12 (0.04–0.24)  12 months 0.22 (0.10–0.36) 0.09 (0.02–0.25) 0.23 (0.15–0.33) 0.12 (0.04–0.24) Non-CNS progression  6 months 0.11 (0.04–0.24) 0.24 (0.09–0.43) 0.25 (0.17–0.35) 0.37 (0.22–0.51)  12 months 0.22 (0.10–0.37) 0.43 (0.22–0.62) 0.35 (0.25–0.45) 0.55 (0.38–0.69) Death  6 months 0.03 (0.00–0.12) 0.05 (0.00–0.19) 0.07 (0.03–0.13) 0.05 (0.01–0.15)  12 months 0.03 (0.00–0.12) 0.05 (0.00–0.19) 0.07 (0.03–0.13) 0.08 (0.02–0.19) Data are given as cumulative incidence probability (95% confidence interval) ALK anaplastic lymphoma kinase, CNS central nervous system, EXP expansion cohort, TKI tyrosine kinase inhibitor With or without chemotherapy Cumulative Incidence Cumulative Incidence 60 T. M. Bauer et al. Fig. 2 Cumulative incidence 1.0 of CNS progression, non-CNS CNS PD 0.9 progression, and death with Non-CNS PD lorlatinib in patients with at 0.8 least one prior second-gener- Death 0.7 ation ALK TKI* (EXP3B–5). 0.6 a Patients with baseline CNS metastases and b patients with- 0.5 out baseline CNS metastases. 0.4 *With or without chemotherapy. 0.3 ALK anaplastic lymphoma kinase, CNS central nervous 0.2 system, EXP expansion cohort, 0.1 PD progressive disease, TKI 0.0 tyrosine kinase inhibitor 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 Time (months) Cumulative no. of events CNS PD 00668 912141517181820202 21 2 Non-CNS PD 006 10 13 17 22 23 25 27 28 28 30 33 36 36 Death 0136666666666 66 6 1.0 0.9 CNS PD Non-CNS PD 0.8 Death 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 Time (months) Cumulative no. of events 00355555555555 5 5 CNS PD 0158 11 12 15 18 19 20 21 21 22 22 23 23 Non-CNS PD Death 00012223333333 3 3 3.4 Antitumor Activity in Irradiated Brain Lesions 3.5 Leptomeningeal Disease/Carcinomatosis with Progression at Baseline Lorlatinib was also active in the two ALK-positive In EXP2–3A, intracranial responses in irradiated brain patients with leptomeningeal disease at baseline. One lesions with progression at baseline were observed in four patient had overall and intracranial responses of complete (50.0%; 95% CI 15.7–84.3) of eight patients and median response, and had not progressed at the time of analysis, duration of intracranial response was not reached (95% CI with an overall time to progression of 21.9 months (in 2.8–not estimable; Fig. 4a; Supplementary Table A.2). Of follow-up for progression). The second patient achieved 30 patients in EXP3B–5, 12 (40.0%; 95% CI 22.7–59.4) overall and intracranial responses of partial response; the achieved an intracranial response in irradiated brain lesions overall time to progression was 11 months. with progression at baseline and median duration of intrac- ranial response was 12.4 months (95% CI 11.1–not estima- ble; Fig. 4b; Supplementary Table A.2). Best responses of 3.6 Safety stable disease in irradiated brain lesions with progression at baseline were observed in three (37.5%) and ten (33.3%) The safety profile of lorlatinib based on the overall phase patients, respectively, with some lasting > 6 months (Fig. 4; II population has been previously reported, with CNS Supplementary Table A.2). effects (e.g., cognitive and mood effects) among the Cumulative Incidence Cumulative Incidence CIRs of CNS and Non-CNS Progression with Lorlatinib in ALK-Positive NSCLC 61 Fig. 3 Cumulative incidence 1.0 of CNS progression, non-CNS CNS PD 0.9 progression, and death with Non-CNS PD 0.8 lorlatinib in patients with a sec- Death ond-generation ALK TKI* as 0.7 their last prior TKI. a Patients 0.6 with baseline CNS metastases 0.5 and b patients without baseline CNS metastases. *Second- 0.4 generation ALK TKIs included: 0.3 alectinib (n = 62), ceritinib 0.2 (n = 47), brigatinib (n = 8); other 0.1 TKI (ensartinib or entrec- tinib) (n = 4). ALK anaplastic 0.0 lymphoma kinase, CNS central 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 nervous system, EXP expansion Time (months) Cumulative no. of events cohort, PD progressive disease, CNS PD 006678 11 13 14 15 16 16 17 17 18 19 TKI tyrosine kinase inhibitor 0048 11 15 20 21 23 25 26 26 27 30 32 32 Non-CNS PD Death 01355555555555 5 5 b 1.0 CNS PD 0.9 Non-CNS PD 0.8 Death 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 Time (months) Cumulative no. of events CNS PD 002444444444444 4 Non-CNS PD 0147 10 11 14 17 17 18 19 19 19 19 20 20 Death 0001222333333 33 3 Table 3 Intracranial antitumor activity by independent central review in patients with ≥ 1 measurable CNS lesion at baseline a a Prior crizotinib (EXP2–3A; n = 24) At least one prior second-generation ALK TKI (EXP3B–5; n = 57) Best overall intracranial response, n (%)  Complete response 6 (25.0) 12 (21.1)  Partial response 15 (62.5) 19 (33.3)  Stable disease 3 (12.5) 17 (29.8)  Objective progression 0 6 (10.5)  Indeterminate 0 3 (5.3) Objective response rate, n (%) 21 (87.5) 31 (54.4)  95% CI 67.6–97.3 40.7–67.6 Duration of intracranial response, months  Median NR 12.4  95% CI 15.2–NE 5.8–NE NE not evaluable, NR not reached With or without chemotherapy Cumulative Incidence Cumulative Incidence 62 T. M. Bauer et al. Fig. 4 Percentage change from baseline in tumor size of previ- ously irradiated brain lesions in progression at baseline*. a Patients with prior crizotinib (EXP2–3A) and b patients with at least one prior second-gen- eration ALK TKI (EXP3B–5). *Based on derived independent central review. With or without chemotherapy. ALK anaplastic lymphoma kinase, EXP expan- sion cohort, PD progressive disease, TKI tyrosine kinase inhibitor most common treatment-related AEs [18]. Treatment- effective management of CNS metastases in ALK-positive related AEs associated with the CNS (any grade) were NSCLC. Our findings indicate that lorlatinib has robust reported in 71 of 131 patients (54.2%) with baseline CNS CNS activity in patients with previously treated ALK- metastases and 33 of 67 patients (49.3%) without baseline positive NSCLC with or without baseline CNS metasta- CNS metastases (Supplementary Table A.3). Grade 3–4 ses whose disease progressed on crizotinib and/or second- treatment-related AEs associated with the CNS occurred generation ALK TKIs. in 2.3% and 7.5% of patients with and without baseline Among patients with baseline CNS metastases previ- CNS metastases, respectively. Cognitive effects (26.0% ously treated with crizotinib or second-generation TKIs, and 19.4%, respectively) and mood effects (16.8% and the CIR of CNS progression at 12 months was relatively 16.4%, respectively) were the most frequently reported low (22–23%), and the cumulative incidence curves indi- treatment-related CNS AEs in patients with or without cate that the probability of extracranial progression was baseline CNS metastases. generally higher than intracranial progression, indicating that lorlatinib is highly active against CNS metastases. Furthermore, as evident by the relatively small increases 4 Discussion in the CIR between 6 and 12 months, protection against progression in the CNS persisted over time with lorlat- Despite impressive initial responses among patients with inib treatment, suggesting that this benefit to the CNS is ALK-positive advanced NSCLC following treatment with durable. A similar analysis with alectinib in crizotinib- the first-generation ALK TKI crizotinib and with second- refractory patients reported a consistently higher CIR of generation ALK TKIs, including ceritinib, alectinib, and CNS progression than non-CNS progression in patients brigatinib, CNS progression remains a clinically signifi- with baseline CNS metastases [20]. In patients without cant problem [5, 7, 8, 19]. Thus, there remains a need for baseline CNS metastases in our study, the higher CIR for CIRs of CNS and Non-CNS Progression with Lorlatinib in ALK-Positive NSCLC 63 non-CNS progression than for CNS progression in both these data suggest lorlatinib may have activity against lep- patient groups indicates that lorlatinib may also prevent tomeningeal disease, which could potentially be explained metastatic spread to the brain in ALK-positive NSCLC. by its high CNS permeability as demonstrated in preclini- This protective effect in patients without baseline CNS cal studies [14, 15]. Other brain-penetrant ALK TKIs, disease was maintained over time, as evidenced by the alectinib and ceritinib, have shown analogous activity in unchanged CIR of CNS progression (9% for EXP2–3A case reports of leptomeningeal carcinomatosis, further and 12% for EXP3B–5) between 6 and 12 months in both substantiating this hypothesis [27, 28]. groups. Although these findings should be interpreted AEs associated with the CNS reported with lorlatinib with caution, given the small patient numbers in some were generally mild to moderate in severity and were com- subgroups and the exploratory post hoc nature of the anal- parable between patients with or without baseline CNS ysis, these data further support the substantial intracranial metastases. Further details on CNS effects associated with antitumor activity seen in patients treated with previous lorlatinib treatment (i.e., changes in cognitive function, crizotinib only or previous second-generation ALK TKIs mood, and speech, and comprehensive guidance on the in this phase II study. Lorlatinib also showed clinically management of the unique AE profile) have been pub - meaningful benefit in previously irradiated brain lesions lished [29]. that were in progression at baseline, a subset of metastases Overall, the results of this analysis show that lorlatinib for which treatment options are limited. Local reirradia- is active in the treatment and prevention of CNS metasta- tion or whole-brain radiotherapy may be considered for ses in patients with ALK-positive NSCLC with or without patients with these metastases; however, neurocognitive baseline CNS metastases whose disease progressed on cri- impairment and decreased quality of life remain signifi- zotinib and/or second-generation ALK TKIs. cant issues with such treatments [21, 22]. Together, our Acknowledgements Medical writing support was provided by Jade findings indicate that the robust CNS activity of lorlat- Drummond and Brian Szente of inScience Communications, Springer inib may assuage the need for additional treatment with Healthcare (Chester, UK and Philadelphia, PA, USA), and was funded local CNS-directed therapies. Thus, lorlatinib represents by Pfizer Inc. a highly effective treatment option for patients who have Author Contributions All authors made substantial contributions to CNS progression on ALK TKIs, including brain-penetrant, the conception and design, or analysis and interpretation of data, and second-generation TKIs. to the drafting of the manuscript or revising it critically for important The generally lower CIRs of CNS progression than non- intellectual content. Additionally, all authors provided final approval CNS progression reported here, together with previously of the version to be submitted. reported efficacy results [18], may suggest that lorlatinib has more durable activity in the CNS than in extracra- Data Sharing Statement Upon request, and subject to certain crite- ria, conditions, and exceptions (see  https ://www .pf ize r .com/scien nial sites. A potential reason for this difference might be ce/clini cal-trial s/trial -data-and-resul ts for more information), Pfizer that CNS lesions have been exposed to fewer therapies will provide access to individual deidentified participant data from at baseline due to the BBB attenuating CNS exposure to Pfizer-sponsored global interventional clinical studies conducted for prior treatments, such as ALK TKIs and chemotherapy, to medicines, vaccines, and medical devices (1) for indications that have been approved in the US and/or EU or (2) in programs that have been varying extents. An analysis of lorlatinib-resistant biop- terminated (ie, development for all indications has been discontinued). sies found an accumulation of ALK resistance mutations Pfizer will also consider requests for the protocol, data dictionary, and through sequential ALK TKIs, suggesting that less expo- statistical analysis plan. Data may be requested from Pfizer trials 24 sure to ALK TKIs may prevent the emergence of muta- months after study completion. The deidentified participant data will be made available to researchers whose proposals meet the research cri- tions that confer resistance to lorlatinib [23]. Thus, it is teria and other conditions, and for which an exception does not apply, tempting to speculate that there would be less mutational via a secure portal. To gain access, data requestors must enter into a heterogeneity in CNS lesions than non-CNS lesions, with data access agreement with Pfizer. fewer resistance mutations having likely developed. Addi- tionally, tumor microenvironments at specific metastatic Compliance with Ethical Standards sites (e.g., brain, lung, and liver) can be widely diverse Funding This study was sponsored by Pfizer Inc. and have been shown to influence response to anti-cancer treatments [24, 25]. Conflict of interest TMB has received fees for consulting/advisory Leptomeningeal carcinomatosis is associated with poor board roles for Guardant Health, Ignyta, Loxo, Moderna Therapeutics, prognosis and, thus, is listed in the exclusion criteria for and Pfizer Inc. ATS has received fees for consulting/advisory board the majority of NSCLC trials [26]. In our study, durable roles from Ariad/Takeda, Bayer, Blueprint Medicines, Chugai, Dai- overall and intracranial responses were observed in both ichi Sankyo, EMD Serono, Genentech, Ignyta, KSQ Therapeutics, Loxo, Natera, Novartis, Pfizer, Roche, Taiho, and TP Therapeutics, patients who presented with leptomeningeal involvement and honoraria from Foundation Medicine, Guardant, Novartis, Pfizer, at baseline. Notwithstanding the small number of patients, 64 T. M. Bauer et al. and Roche. AN has received fees for consult/advisory board roles from (ASCEND-4): a randomised, open-label, phase 3 study. Lan- Boehringer Ingelheim, Roche, Pfizer, Bristol-Myers Squibb, Oryzon cet. 2017;389(10072):917–29. https ://doi.org/10.1016/S0140 Genomics and travel expenses from Pfizer and Boehringer Ingelheim. -6736(17)30123 -X. MLJ has nothing to disclose. JFG has received fees for consulting/ 9. Costa DB, Shaw AT, Ou SH, Solomon BJ, Riely GJ, Ahn advisory board roles from Bristol-Myers Squibb, Genentech/Roche, MJ, et al. Clinical experience with crizotinib in patients with Novartis, Loxo, Theravance, Clovis, Merck, Boehringer Ingelheim, advanced ALK-rearranged non-small-cell lung cancer and and Incyte. HT, GP, YKP, and AA own stock in and are employees brain metastases. J Clin Oncol. 2015;33(17):1881–8. https :// of Pfizer. EF has received fees for consulting/advisory board roles for doi.org/10.1200/JCO.2014.59.0539. Celgene, Eli Lilly, Guardant Health, and Takeda, and has served as a 10. Katayama R, Shaw AT, Khan TM, Mino-Kenudson M, Solo- consultant and on the speakers’ bureau for AstraZeneca, Boehringer mon BJ, Halmos B, et  al. Mechanisms of acquired crizotinib Ingelheim, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, resistance in ALK-rearranged lung cancers. Sci Transl Med. Pfizer, and Roche. 2012;4(120):120ra117. https ://doi.or g/10.1126/scitr anslm ed.30033 16. 11. Solomon BJ, Cappuzzo F, Felip E, Blackhall FH, Costa DB, Open Access This article is licensed under a Creative Commons Attri- Kim DW, et al. Intracranial efficacy of crizotinib versus chem- bution-NonCommercial 4.0 International License, which permits any otherapy in patients with advanced ALK-positive non-small- non-commercial use, sharing, adaptation, distribution and reproduction cell lung cancer: results from PROFILE 1014. J Clin Oncol. in any medium or format, as long as you give appropriate credit to the 2016;34(24):2858–65. https://doi.or g/10.1200/JCO.2015.63.5888. original author(s) and the source, provide a link to the Creative Com- 12. Costa DB, Kobayashi S, Pandya SS, Yeo WL, Shen Z, Tan W, mons licence, and indicate if changes were made. The images or other et  al. 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Brain Penetration of Lorlatinib: Cumulative Incidences of CNS and Non-CNS Progression with Lorlatinib in Patients with Previously Treated ALK-Positive Non-Small-Cell Lung Cancer

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1776-2596
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10.1007/s11523-020-00702-4
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Abstract

Background Lorlatinib is a potent, third-generation ALK/ROS1 tyrosine kinase inhibitor (TKI) designed to penetrate the blood–brain barrier. Objective We report the cumulative incidence of central nervous system (CNS) and non-CNS progression with lorlatinib in patients with ALK-positive non-small-cell lung cancer (NSCLC) previously treated with ALK TKIs. Patients and methods In an ongoing phase II study (NCT01970865), 198 patients with ALK-positive NSCLC with ≥ 1 prior ALK TKI were enrolled into expansion cohorts (EXP) based on treatment history. Patients received lorlatinib 100 mg once daily. Patients were analyzed for progressive disease, categorized as CNS or non-CNS progression, by independent central review. Cumulative incidence probabilities were calculated adopting a competing risks approach. Results Fifty-nine patients received crizotinib as their only prior ALK TKI (EXP2–3A); cumulative incidence rates (CIRs) of CNS and non-CNS progression were both 22% at 12 months in patients with baseline CNS metastases (n = 37), and CIR of non-CNS progression at 12 months was higher versus that for CNS progression in patients without baseline CNS metas- tases [43% vs. 9% (n = 22)]. In patients who received ≥ 1 prior second-generation ALK TKI [EXP3B–5 (n = 139)], CIR of non-CNS progression at 12 months was higher versus that for CNS progression in patients both with and without baseline CNS metastases (35% vs. 23% (n = 94) and 55% vs. 12% (n = 45), respectively). Conclusions Lorlatinib showed substantial intracranial activity in patients with pretreated ALK-positive NSCLC, with or without baseline CNS metastases, whose disease progressed on crizotinib or second-generation ALK TKIs. ClinicalTrials.gov identifier NCT01970865. Key Points Prior presentation Some of the results from these analyses have been presented at the International Association for the Study of Lung Cancer (IASLC) 19th World Conference on Lung Cancer Lorlatinib is a potent, brain-penetrant, third-generation (WCLC), 23–26 September 2018; Toronto, Ontario, Canada; ALK/ROS1 TKI. American Society of Clinical Oncology (ASCO) meeting 1–5 June 2018, Chicago, Illinois, USA, and European Medical Society We performed an analysis of CNS and non-CNS pro- for Oncology (ESMO) meeting, 27 September–1 October 2019, gression in patients with pretreated ALK+ NSCLC. Barcelona, Spain. Our results indicate that lorlatinib is active in the treat- Electronic supplementary material The online version of this ment and prevention of CNS metastases in patients with article (https ://doi.org/10.1007/s1152 3-020-00702 -4) contains ALK+ NSCLC, including those who had progressed on supplementary material, which is available to authorized users. crizotinib or second-generation TKIs. * Todd M. Bauer tbauer@tnonc.com Vall d’Hebron University Hospital, Vall d’Hebron Institute of Oncology (VHIO), Passeig de la Vall d’Hebron, 119-129, Sarah Cannon Cancer Research Institute/Tennessee 08035 Barcelona, Spain Oncology, PLLC, 250 25th Ave N, Nashville, TN 37203, Pfizer Oncology, 10777 Science Center Dr, La Jolla, CA, USA USA Pfizer Oncology, Via Anna Maria Mozzoni, 12, Milan, Italy Massachusetts General Hospital, 55 Fruit St, Boston, MA 02114, USA Pfizer Oncology, 280 Shennecossett Rd, Groton, CT, USA Vol.:(0123456789) 56 T. M. Bauer et al. non-CNS progression in patients with ALK-positive NSCLC 1 Introduction previously treated with ALK TKIs from the phase II portion of the phase I/II study. We also present antitumor activity Central nervous system (CNS) metastases are a known data in previously irradiated brain lesions with progression complication of anaplastic lymphoma kinase (ALK)-pos- at baseline and in patients with leptomeningeal disease. itive non-small-cell lung cancer (NSCLC), occurring in approximately 30% of patients at the time of diagnosis [1]. In general, the presence of CNS metastases is associated 2 Materials and Methods with a poor prognosis, including decreased progression-free survival, and can lead to neurocognitive dysfunction that can 2.1 Study Design and Participants negatively affect patient quality of life [2 –4]. ALK tyrosine kinase inhibitors (TKIs), including the The full methodology for this ongoing, open-label, single- first-generation TKI crizotinib [5 ] and second-generation arm, multicenter phase II trial has been published [18]. ALK TKIs [6–8], are standard therapies for patients with Eligible patients were aged ≥ 18 years and had histologi- ALK-positive NSCLC. However, most patients treated with cally or cytologically confirmed metastatic NSCLC with crizotinib will relapse over time because of the development either ALK or ROS1 rearrangement. ALK positivity was of resistance and poor intracranial disease control [9–11]. determined locally on the basis of the US Food and Drug The CNS is a common site of progression with crizotinib, Administration-approved fluorescence in  situ hybridiza- likely because of poor CNS penetration as a result of P-gly- tion assay (Abbott Molecular, Abbott Park, IL, USA) or by coprotein-mediated efflux across the blood–brain barrier immunohistochemistry (Ventana Medical Systems, Tucson, (BBB) [12]. Despite the development of more potent and AZ, USA). An Eastern Cooperative Oncology Group per- BBB-permeable second-generation ALK TKIs, the emer- formance status of ≤ 2 and ≥ 1 measurable target extrac- gence of resistance and progression of CNS metastases ranial lesion according to Response Evaluation Criteria in remain clinically significant issues in the management of Solid Tumors (RECIST), version 1.1, were also required. ALK-positive NSCLC. Patients with untreated or treated (including those con- Lorlatinib was specifically designed to penetrate the BBB trolled with stable or decreasing steroid use within the last and is a highly potent, selective, third-generation macrocy- 2 weeks) asymptomatic CNS metastases were permitted. clic inhibitor of ALK and ROS1 with broad ALK mutational CNS metastases may be newly diagnosed or be present as coverage [13]. Using radiolabeling and positron emission progressive disease after surgery, whole-brain radiotherapy, tomography imaging, lorlatinib demonstrated high BBB or stereotactic radiosurgery. Prior radiotherapy must have permeability and rapid brain uptake in animals [14, 15]. been completed within 2 weeks of study entry (whole-brain Lorlatinib has also shown antitumor activity in ALK-posi- radiotherapy: ≤ 4 weeks). Patients with leptomeningeal dis- tive intracranial tumor models [16]. The high CNS penetra- ease/carcinomatosis were allowed to enroll if the disease tion of lorlatinib noted in preclinical studies was confirmed was visualized on magnetic resonance imaging (MRI) or if in the clinic where the mean ratio of cerebrospinal fluid baseline CSF-positive cytology was available. (CSF)/plasma (unbound) was 0.75 in four patients, who had Patients were enrolled into expansion cohorts (EXP) by matched samples available, from the phase I portion of the their ALK (EXP1–5) or ROS1 (EXP6) status and treatment ongoing phase I/II study (NCT01970865) [17]. This phase history. In this analysis, we focused on previously treated I/II study demonstrated robust overall and intracranial anti- ALK-positive patients who were enrolled into EXP2–5. tumor activity of lorlatinib in patients with ALK-positive Specific enrolment criteria for these ALK-positive cohorts NSCLC, most of whom had CNS metastases at baseline were as follows: progression following previous crizotinib and experienced treatment failure with ≥ 1 ALK TKI [17, only (EXP2), progression following previous crizotinib and 18]. On the basis of data from this phase I/II study, the US one or two regimens of chemotherapy given before or after Food and Drug Administration granted lorlatinib acceler- crizotinib (EXP3A), progression following one previous ated approval status in November 2018 for the treatment second-generation ALK TKI with or without chemotherapy of patients with ALK-positive metastatic NSCLC who had (EXP3B), and ALK-positive patients with disease progres- disease progression on crizotinib and ≥ 1 other ALK TKI sion following two (EXP4) or three (EXP5) previous ALK or who had disease progression on alectinib or ceritinib as TKIs with or without chemotherapy. the first ALK TKI received. In May 2019, the European Patients were administered lorlatinib orally at a dose of Commission also approved lorlatinib for use in these patient 100 mg once daily until progression, unacceptable toxicity, populations. death, or withdrawal. Treatment beyond progression was To further assess the effect of brain penetration with permitted if the patient was still experiencing clinical benefit lorlatinib in the clinic, we report an analysis of CNS and per the investigator’s discretion. CIRs of CNS and Non-CNS Progression with Lorlatinib in ALK-Positive NSCLC 57 All patients provided written, informed consent before Other efficacy and statistical methodology has been previ- participation. The institutional review board or independ- ously described [18]. The data cutoff for this analysis was ent ethics committee at each participating site approved 2 February 2018. the protocol, which complied with the International Ethi- cal Guidelines for Biomedical Research Involving Human Subjects, Good Clinical Practice guidelines, the Declaration of Helsinki, and local laws.3 Results 2.2 Assessments3.1 Patients All patients underwent baseline tumor imaging by computed Patients were enrolled between 15 September 2015, and 3 tomography and brain imaging by MRI. Computed tomog- October 2016. Baseline characteristics of the overall phase raphy and MRI scans were to be taken every 6 weeks for the II population (EXP1–6) have been previously reported first 30 months and then every 12 weeks thereafter until pro- [18]. In this analysis, we report data from the 198 patients gressive disease or the start of a new anticancer treatment. with ALK-positive NSCLC who had received ≥ 1 ALK Response was assessed according to modified RECIST, ver - TKI and received ≥ 1 dose of lorlatinib (EXP2–5). Of these sion 1.1, which allowed for up to five CNS target lesions, patients, 59 received crizotinib as their only prior ALK as assessed by independent central radiology review (ICR). TKI (EXP2–3A) and 139 received ≥ 1 prior second-gen- Adverse events (AEs) associated with the CNS were ana- eration ALK TKI (EXP3B–5). Baseline CNS metastases lyzed. They consisted of preferred terms from the Medical (measurable/non-measurable) were present in 37 patients Dictionary for Regulatory Activities System Organ Class (62.7%) from EXP2–3A and in 94 patients (67.6%) from (SOC) of psychiatric disorders and SOC of nervous system EXP3B–5. Baseline characteristics of the subgroups ana- disorders. Peripheral neuropathy was excluded as it repre- lyzed are shown in Table 1 and were generally comparable. sented an AE associated with the peripheral nervous sys- There were more Asian patients (51.1%) and fewer White tem, but not the CNS. These AEs were assessed at baseline, patients (33.3%) in the EXP3B–5 subgroup without base- every subsequent visit, and ≥ 28 days after the final lorlatinib line CNS metastases compared with all other subgroups administration, and were graded according to the National (27.0–31.8% and 50.0–54.3%, respectively). Among Cancer Institute Common Terminology Criteria for Adverse patients with baseline CNS metastases in EXP2–3A and Events, version 4.03. EXP3B–5, respectively, eight (21.6%) and 30 (31.9%) had irradiated brain lesions with progression at baseline; 2.3 Statistical Analysis the median number was 3.5 lesions (range 2–10) and 5.0 lesions (range 1–11) per patient. At the time of data cut- Patients were analyzed for progressive disease events, cat- off, the median duration of follow-up for progression-free egorized as either CNS or non-CNS progression, by ICR. survival for EXP2–3A and EXP3B–5 was 18.2  months Any new CNS lesions or progression of pre-existing CNS (95% confidence interval (CI) 18.0–21.1 months) and 19.1 lesions versus baseline was considered a CNS progres- months (95% CI 16.5–20.8 months), respectively. sion, while any new lesion or progression of pre-existing lesions in areas outside the CNS was considered non-CNS 3.2 CNS Versus Non‑CNS Progression progression. If both CNS and non-CNS progression were presented simultaneously as the first progressive event, Figure  1 shows the cumulative incidences for CNS pro- patients were considered to have CNS progression as their gression, non-CNS progression, and death with lorlatinib first event. The probability of a first event being a CNS pro- in patients who had received prior crizotinib as their only gression, non-CNS progression, or death was estimated by ALK TKI (EXP2–3A). In patients with baseline CNS metas- cumulative incidences using a competing risks approach in tases (n = 37), the cumulative incidence rates (CIRs) of CNS patients with or without baseline CNS metastases. EXP2 and non-CNS progression were 16% and 11% at 6 months, and EXP3A were pooled because the included patients had respectively, and 22% and 22% at 12 months, respectively all been treated with crizotinib (first-generation ALK TKI) (Fig. 1a; Table 2). In patients without baseline CNS metas- as their only prior ALK TKI. EXP3B, EXP4, and EXP5 tases (n = 22), the CIR of non-CNS progression was higher were pooled because the included patients had all received versus that for CNS progression at both 6 months (24% vs. ≥ 1 prior second-generation ALK TKI. 9%) and 12 months (43% vs. 9%; Fig. 1b and Table 2). In an unplanned subgroup analysis, intracranial In patients who had received ≥ 1 prior second-gener- response was derived based on irradiated brain lesions ation ALK TKI (EXP3B–5) with baseline CNS metasta- with progression at baseline and new brain lesions only. ses (n = 94), the CIR of non-CNS progression was higher 58 T. M. Bauer et al. Table 1 Baseline characteristics of the pooled subgroups for this analysis by baseline metastases a a CharacteristicPrior crizotinib (EXP2–3A; n = 59) At least one prior second-generation ALK TKI (EXP3B–5; n = 139) Baseline CNS metastases No baseline CNS metastases Baseline CNS metastases No baseline b b (n = 37) (n = 22) (n = 94) CNS metastases (n = 45) Age, years  Median 54.0 58.0 50.5 56.0  Range 30–74 37–85 29–77 33–83 Sex, n (%)  Male 12 (32.4) 8 (36.4) 40 (42.6) 21 (46.7)  Female 25 (67.6) 14 (63.6) 54 (57.4) 24 (53.3) Race, n (%)  White 20 (54.1) 11 (50.0) 51 (54.3) 15 (33.3)  Asian 10 (27.0) 7 (31.8) 30 (31.9) 23 (51.1)  Black 0 0 0 1 (2.2)  Other 1 (2.7) 1 (4.5) 4 (4.3) 2 (4.4)  Not specified 6 (16.2) 3 (13.6) 9 (9.6) 4 (8.9) ECOG PS, n (%)  0 17 (45.9) 11 (50.0) 45 (47.9) 16 (35.6)  1 20 (54.1) 10 (45.5) 44 (46.8) 28 (62.2)  2 0 1 (4.5) 5 (5.3) 1 (2.2) Irradiated brain lesions with progression at screening  n (%) 8 (21.6) 30 (31.9)  Number of lesions,   Median 3.5 5.0   Range 2–10 1–11 ALK anaplastic lymphoma kinase, CNS central nervous system, ECOG PS Eastern Cooperative Oncology Group performance status, EXP expansion cohort, TKI tyrosine kinase inhibitor With or without chemotherapy Includes patients with measurable and/or non-measurable CNS lesions Number of patients with irradiated brain lesions with progression at screening by independent central review versus that for CNS progression at 6  months (25% vs. metastases at 6 months (27% vs. 15% and 38% vs. 11%, 14%) and at 12 months (35% vs. 23%; Fig. 2a; Table 2). respectively) and at 12 months (37% vs. 23% and 53% vs. Patients without baseline CNS metastases (n = 45) also had 11%, respectively; Supplementary Table A.1). a higher CIR of non-CNS progression versus that for CNS progression, with CIRs of 37% versus 12% at 6 months and 3.3 Intracranial Antitumor Activity 55% versus 12% at 12 months (Fig. 2b; Table 2). Of all patients previously treated with ≥ 1 prior second- Baseline measurable CNS metastases were present in 24 generation ALK TKI, 121 of 139 received a second-gen- (64.9%) out of 37 patients in EXP2–3A and 57 (60.6%) eration ALK TKI as their last ALK TKI prior to receiving out of 94 patients in EXP3B–5. In EXP2–3A, intracranial lorlatinib, with most having last received alectinib (n = 62) responses were observed in 21 (87.5%, 95% CI 67.6–97.3) or ceritinib (n = 47). The curves of cumulative incidence of 24 patients (Table 3). Median duration of response was for CNS and non-CNS progression were similar to those not reached (95% CI 15.2 months–not estimable). Of the for the overall EXP3B–5 subgroups (Fig. 3). Similarly, the 57 patients in EXP3B–5, 31 (54.4%; 95% CI 40.7–67.6) CIR of non-CNS progression was higher versus that for achieved an intracranial response and the median duration CNS progression in patients with or without baseline CNS of response was 12.4 months (95% CI 5.8–not estimable). CIRs of CNS and Non-CNS Progression with Lorlatinib in ALK-Positive NSCLC 59 Fig. 1 Cumulative incidence 1.0 of CNS progression, non-CNS CNS PD 0.9 progression, and death with lor- Non-CNS PD latinib in patients with prior cri- 0.8 zotinib* (EXP2–3A). a Patients Death 0.7 with baseline CNS metastases and b patients without baseline 0.6 CNS metastases. *With or with- 0.5 out chemotherapy. CNS central 0.4 nervous system, EXP expansion cohort, PD progressive disease 0.3 0.2 0.1 0.0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 Time (months) Cumulative no. of events CNS PD 00233368888888 8 8 Non-CNS PD 00001244455789 10 10 Death 0001111111111 11 1 1.0 0.9 CNS PD 0.8 Non-CNS PD 0.7 Death 0.6 0.5 0.4 0.3 0.2 0.1 0.0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 Time (months) Cumulative no. of events CNS PD 00222222222222 2 2 001114555699 9101 10 0 Non-CNS PD Death 00 111 11 11 11 11 11 1 Table 2 Cumulative incidence probabilities for CNS progression, non-CNS progression, and death at 6 and 12 months a a Prior crizotinib (EXP2–3A; n = 59) At least one prior second-generation ALK TKI (EXP3B–5; n = 139) Baseline CNS metastases No baseline CNS metastases Baseline CNS metastases No baseline CNS (n = 37) (n = 22) (n = 94) metastases (n = 45) CNS progression  6 months 0.16 (0.07–0.30) 0.09 (0.02–0.25) 0.14 (0.07–0.22) 0.12 (0.04–0.24)  12 months 0.22 (0.10–0.36) 0.09 (0.02–0.25) 0.23 (0.15–0.33) 0.12 (0.04–0.24) Non-CNS progression  6 months 0.11 (0.04–0.24) 0.24 (0.09–0.43) 0.25 (0.17–0.35) 0.37 (0.22–0.51)  12 months 0.22 (0.10–0.37) 0.43 (0.22–0.62) 0.35 (0.25–0.45) 0.55 (0.38–0.69) Death  6 months 0.03 (0.00–0.12) 0.05 (0.00–0.19) 0.07 (0.03–0.13) 0.05 (0.01–0.15)  12 months 0.03 (0.00–0.12) 0.05 (0.00–0.19) 0.07 (0.03–0.13) 0.08 (0.02–0.19) Data are given as cumulative incidence probability (95% confidence interval) ALK anaplastic lymphoma kinase, CNS central nervous system, EXP expansion cohort, TKI tyrosine kinase inhibitor With or without chemotherapy Cumulative Incidence Cumulative Incidence 60 T. M. Bauer et al. Fig. 2 Cumulative incidence 1.0 of CNS progression, non-CNS CNS PD 0.9 progression, and death with Non-CNS PD lorlatinib in patients with at 0.8 least one prior second-gener- Death 0.7 ation ALK TKI* (EXP3B–5). 0.6 a Patients with baseline CNS metastases and b patients with- 0.5 out baseline CNS metastases. 0.4 *With or without chemotherapy. 0.3 ALK anaplastic lymphoma kinase, CNS central nervous 0.2 system, EXP expansion cohort, 0.1 PD progressive disease, TKI 0.0 tyrosine kinase inhibitor 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 Time (months) Cumulative no. of events CNS PD 00668 912141517181820202 21 2 Non-CNS PD 006 10 13 17 22 23 25 27 28 28 30 33 36 36 Death 0136666666666 66 6 1.0 0.9 CNS PD Non-CNS PD 0.8 Death 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 Time (months) Cumulative no. of events 00355555555555 5 5 CNS PD 0158 11 12 15 18 19 20 21 21 22 22 23 23 Non-CNS PD Death 00012223333333 3 3 3.4 Antitumor Activity in Irradiated Brain Lesions 3.5 Leptomeningeal Disease/Carcinomatosis with Progression at Baseline Lorlatinib was also active in the two ALK-positive In EXP2–3A, intracranial responses in irradiated brain patients with leptomeningeal disease at baseline. One lesions with progression at baseline were observed in four patient had overall and intracranial responses of complete (50.0%; 95% CI 15.7–84.3) of eight patients and median response, and had not progressed at the time of analysis, duration of intracranial response was not reached (95% CI with an overall time to progression of 21.9 months (in 2.8–not estimable; Fig. 4a; Supplementary Table A.2). Of follow-up for progression). The second patient achieved 30 patients in EXP3B–5, 12 (40.0%; 95% CI 22.7–59.4) overall and intracranial responses of partial response; the achieved an intracranial response in irradiated brain lesions overall time to progression was 11 months. with progression at baseline and median duration of intrac- ranial response was 12.4 months (95% CI 11.1–not estima- ble; Fig. 4b; Supplementary Table A.2). Best responses of 3.6 Safety stable disease in irradiated brain lesions with progression at baseline were observed in three (37.5%) and ten (33.3%) The safety profile of lorlatinib based on the overall phase patients, respectively, with some lasting > 6 months (Fig. 4; II population has been previously reported, with CNS Supplementary Table A.2). effects (e.g., cognitive and mood effects) among the Cumulative Incidence Cumulative Incidence CIRs of CNS and Non-CNS Progression with Lorlatinib in ALK-Positive NSCLC 61 Fig. 3 Cumulative incidence 1.0 of CNS progression, non-CNS CNS PD 0.9 progression, and death with Non-CNS PD 0.8 lorlatinib in patients with a sec- Death ond-generation ALK TKI* as 0.7 their last prior TKI. a Patients 0.6 with baseline CNS metastases 0.5 and b patients without baseline CNS metastases. *Second- 0.4 generation ALK TKIs included: 0.3 alectinib (n = 62), ceritinib 0.2 (n = 47), brigatinib (n = 8); other 0.1 TKI (ensartinib or entrec- tinib) (n = 4). ALK anaplastic 0.0 lymphoma kinase, CNS central 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 nervous system, EXP expansion Time (months) Cumulative no. of events cohort, PD progressive disease, CNS PD 006678 11 13 14 15 16 16 17 17 18 19 TKI tyrosine kinase inhibitor 0048 11 15 20 21 23 25 26 26 27 30 32 32 Non-CNS PD Death 01355555555555 5 5 b 1.0 CNS PD 0.9 Non-CNS PD 0.8 Death 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 Time (months) Cumulative no. of events CNS PD 002444444444444 4 Non-CNS PD 0147 10 11 14 17 17 18 19 19 19 19 20 20 Death 0001222333333 33 3 Table 3 Intracranial antitumor activity by independent central review in patients with ≥ 1 measurable CNS lesion at baseline a a Prior crizotinib (EXP2–3A; n = 24) At least one prior second-generation ALK TKI (EXP3B–5; n = 57) Best overall intracranial response, n (%)  Complete response 6 (25.0) 12 (21.1)  Partial response 15 (62.5) 19 (33.3)  Stable disease 3 (12.5) 17 (29.8)  Objective progression 0 6 (10.5)  Indeterminate 0 3 (5.3) Objective response rate, n (%) 21 (87.5) 31 (54.4)  95% CI 67.6–97.3 40.7–67.6 Duration of intracranial response, months  Median NR 12.4  95% CI 15.2–NE 5.8–NE NE not evaluable, NR not reached With or without chemotherapy Cumulative Incidence Cumulative Incidence 62 T. M. Bauer et al. Fig. 4 Percentage change from baseline in tumor size of previ- ously irradiated brain lesions in progression at baseline*. a Patients with prior crizotinib (EXP2–3A) and b patients with at least one prior second-gen- eration ALK TKI (EXP3B–5). *Based on derived independent central review. With or without chemotherapy. ALK anaplastic lymphoma kinase, EXP expan- sion cohort, PD progressive disease, TKI tyrosine kinase inhibitor most common treatment-related AEs [18]. Treatment- effective management of CNS metastases in ALK-positive related AEs associated with the CNS (any grade) were NSCLC. Our findings indicate that lorlatinib has robust reported in 71 of 131 patients (54.2%) with baseline CNS CNS activity in patients with previously treated ALK- metastases and 33 of 67 patients (49.3%) without baseline positive NSCLC with or without baseline CNS metasta- CNS metastases (Supplementary Table A.3). Grade 3–4 ses whose disease progressed on crizotinib and/or second- treatment-related AEs associated with the CNS occurred generation ALK TKIs. in 2.3% and 7.5% of patients with and without baseline Among patients with baseline CNS metastases previ- CNS metastases, respectively. Cognitive effects (26.0% ously treated with crizotinib or second-generation TKIs, and 19.4%, respectively) and mood effects (16.8% and the CIR of CNS progression at 12 months was relatively 16.4%, respectively) were the most frequently reported low (22–23%), and the cumulative incidence curves indi- treatment-related CNS AEs in patients with or without cate that the probability of extracranial progression was baseline CNS metastases. generally higher than intracranial progression, indicating that lorlatinib is highly active against CNS metastases. Furthermore, as evident by the relatively small increases 4 Discussion in the CIR between 6 and 12 months, protection against progression in the CNS persisted over time with lorlat- Despite impressive initial responses among patients with inib treatment, suggesting that this benefit to the CNS is ALK-positive advanced NSCLC following treatment with durable. A similar analysis with alectinib in crizotinib- the first-generation ALK TKI crizotinib and with second- refractory patients reported a consistently higher CIR of generation ALK TKIs, including ceritinib, alectinib, and CNS progression than non-CNS progression in patients brigatinib, CNS progression remains a clinically signifi- with baseline CNS metastases [20]. In patients without cant problem [5, 7, 8, 19]. Thus, there remains a need for baseline CNS metastases in our study, the higher CIR for CIRs of CNS and Non-CNS Progression with Lorlatinib in ALK-Positive NSCLC 63 non-CNS progression than for CNS progression in both these data suggest lorlatinib may have activity against lep- patient groups indicates that lorlatinib may also prevent tomeningeal disease, which could potentially be explained metastatic spread to the brain in ALK-positive NSCLC. by its high CNS permeability as demonstrated in preclini- This protective effect in patients without baseline CNS cal studies [14, 15]. Other brain-penetrant ALK TKIs, disease was maintained over time, as evidenced by the alectinib and ceritinib, have shown analogous activity in unchanged CIR of CNS progression (9% for EXP2–3A case reports of leptomeningeal carcinomatosis, further and 12% for EXP3B–5) between 6 and 12 months in both substantiating this hypothesis [27, 28]. groups. Although these findings should be interpreted AEs associated with the CNS reported with lorlatinib with caution, given the small patient numbers in some were generally mild to moderate in severity and were com- subgroups and the exploratory post hoc nature of the anal- parable between patients with or without baseline CNS ysis, these data further support the substantial intracranial metastases. Further details on CNS effects associated with antitumor activity seen in patients treated with previous lorlatinib treatment (i.e., changes in cognitive function, crizotinib only or previous second-generation ALK TKIs mood, and speech, and comprehensive guidance on the in this phase II study. Lorlatinib also showed clinically management of the unique AE profile) have been pub - meaningful benefit in previously irradiated brain lesions lished [29]. that were in progression at baseline, a subset of metastases Overall, the results of this analysis show that lorlatinib for which treatment options are limited. Local reirradia- is active in the treatment and prevention of CNS metasta- tion or whole-brain radiotherapy may be considered for ses in patients with ALK-positive NSCLC with or without patients with these metastases; however, neurocognitive baseline CNS metastases whose disease progressed on cri- impairment and decreased quality of life remain signifi- zotinib and/or second-generation ALK TKIs. cant issues with such treatments [21, 22]. Together, our Acknowledgements Medical writing support was provided by Jade findings indicate that the robust CNS activity of lorlat- Drummond and Brian Szente of inScience Communications, Springer inib may assuage the need for additional treatment with Healthcare (Chester, UK and Philadelphia, PA, USA), and was funded local CNS-directed therapies. Thus, lorlatinib represents by Pfizer Inc. a highly effective treatment option for patients who have Author Contributions All authors made substantial contributions to CNS progression on ALK TKIs, including brain-penetrant, the conception and design, or analysis and interpretation of data, and second-generation TKIs. to the drafting of the manuscript or revising it critically for important The generally lower CIRs of CNS progression than non- intellectual content. Additionally, all authors provided final approval CNS progression reported here, together with previously of the version to be submitted. reported efficacy results [18], may suggest that lorlatinib has more durable activity in the CNS than in extracra- Data Sharing Statement Upon request, and subject to certain crite- ria, conditions, and exceptions (see  https ://www .pf ize r .com/scien nial sites. A potential reason for this difference might be ce/clini cal-trial s/trial -data-and-resul ts for more information), Pfizer that CNS lesions have been exposed to fewer therapies will provide access to individual deidentified participant data from at baseline due to the BBB attenuating CNS exposure to Pfizer-sponsored global interventional clinical studies conducted for prior treatments, such as ALK TKIs and chemotherapy, to medicines, vaccines, and medical devices (1) for indications that have been approved in the US and/or EU or (2) in programs that have been varying extents. An analysis of lorlatinib-resistant biop- terminated (ie, development for all indications has been discontinued). sies found an accumulation of ALK resistance mutations Pfizer will also consider requests for the protocol, data dictionary, and through sequential ALK TKIs, suggesting that less expo- statistical analysis plan. Data may be requested from Pfizer trials 24 sure to ALK TKIs may prevent the emergence of muta- months after study completion. The deidentified participant data will be made available to researchers whose proposals meet the research cri- tions that confer resistance to lorlatinib [23]. Thus, it is teria and other conditions, and for which an exception does not apply, tempting to speculate that there would be less mutational via a secure portal. To gain access, data requestors must enter into a heterogeneity in CNS lesions than non-CNS lesions, with data access agreement with Pfizer. fewer resistance mutations having likely developed. Addi- tionally, tumor microenvironments at specific metastatic Compliance with Ethical Standards sites (e.g., brain, lung, and liver) can be widely diverse Funding This study was sponsored by Pfizer Inc. and have been shown to influence response to anti-cancer treatments [24, 25]. Conflict of interest TMB has received fees for consulting/advisory Leptomeningeal carcinomatosis is associated with poor board roles for Guardant Health, Ignyta, Loxo, Moderna Therapeutics, prognosis and, thus, is listed in the exclusion criteria for and Pfizer Inc. ATS has received fees for consulting/advisory board the majority of NSCLC trials [26]. In our study, durable roles from Ariad/Takeda, Bayer, Blueprint Medicines, Chugai, Dai- overall and intracranial responses were observed in both ichi Sankyo, EMD Serono, Genentech, Ignyta, KSQ Therapeutics, Loxo, Natera, Novartis, Pfizer, Roche, Taiho, and TP Therapeutics, patients who presented with leptomeningeal involvement and honoraria from Foundation Medicine, Guardant, Novartis, Pfizer, at baseline. Notwithstanding the small number of patients, 64 T. M. Bauer et al. and Roche. AN has received fees for consult/advisory board roles from (ASCEND-4): a randomised, open-label, phase 3 study. Lan- Boehringer Ingelheim, Roche, Pfizer, Bristol-Myers Squibb, Oryzon cet. 2017;389(10072):917–29. https ://doi.org/10.1016/S0140 Genomics and travel expenses from Pfizer and Boehringer Ingelheim. -6736(17)30123 -X. MLJ has nothing to disclose. JFG has received fees for consulting/ 9. Costa DB, Shaw AT, Ou SH, Solomon BJ, Riely GJ, Ahn advisory board roles from Bristol-Myers Squibb, Genentech/Roche, MJ, et al. Clinical experience with crizotinib in patients with Novartis, Loxo, Theravance, Clovis, Merck, Boehringer Ingelheim, advanced ALK-rearranged non-small-cell lung cancer and and Incyte. HT, GP, YKP, and AA own stock in and are employees brain metastases. J Clin Oncol. 2015;33(17):1881–8. https :// of Pfizer. EF has received fees for consulting/advisory board roles for doi.org/10.1200/JCO.2014.59.0539. Celgene, Eli Lilly, Guardant Health, and Takeda, and has served as a 10. Katayama R, Shaw AT, Khan TM, Mino-Kenudson M, Solo- consultant and on the speakers’ bureau for AstraZeneca, Boehringer mon BJ, Halmos B, et  al. Mechanisms of acquired crizotinib Ingelheim, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, resistance in ALK-rearranged lung cancers. Sci Transl Med. 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CSF concentration of the anaplastic lymphoma kinase third party material in this article are included in the article’s Creative inhibitor crizotinib. J Clin Oncol. 2011;29(15):e443–5. https :// Commons licence, unless indicated otherwise in a credit line to the doi.org/10.1200/JCO.2010.34.1313. material. If material is not included in the article’s Creative Commons 13. Johnson TW, Richardson PF, Bailey S, Brooun A, Burke BJ, Col- licence and your intended use is not permitted by statutory regula- lins MR, et al. 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Targeted Oncology – Springer Journals

Published: Feb 14, 2020

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