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Lorlatinib for Previously Treated ALK-Positive Advanced NSCLC: Primary Efficacy and Safety From a Phase 2 Study in People’s Republic of China

Open AccessPublished:March 17, 2022DOI:https://doi.org/10.1016/j.jtho.2022.02.014

      Abstract

      Introduction

      Lorlatinib was found to have activity in ALK-positive NSCLC in a global phase 1 and 2 study. We report an ongoing phase 2 study in Chinese patients with ALK-positive advanced or metastatic NSCLC.

      Methods

      Open-label, dual-cohort study (NCT03909971); patients had progressive disease after ALK tyrosine kinase inhibitor treatment (cohort 1: previous crizotinib; cohort 2: one ALK tyrosine kinase inhibitor other than crizotinib [±prior crizotinib]), more than or equal to one unirradiated extracranial target lesion, and Eastern Cooperative Oncology Group performance status of 0 to 2. Patients received oral lorlatinib 100 mg once daily in continuous 21-day cycles. Primary end point: objective response in cohort 1 by independent central radiology (ICR) according to Response Evaluation Criteria in Solid Tumors version 1.1. Analyses were based on patients receiving more than or equal to one dose.

      Results

      At data cutoff (August 10, 2020), 109 patients were enrolled (cohort 1: n = 67; cohort 2: n = 42). A total of 47 patients in cohort 1 (70.1%, 95% confidence interval [CI]: 57.7–80.7, p < 0.0001; primary end point) and 20 patients in cohort 2 (47.6%, 95% CI: 32.0–63.6, secondary end point) achieved objective response by ICR. Median progression-free survival was not reached in cohort 1 and was 5.6 months in cohort 2. In patients with brain lesions at baseline, 29 of 36 patients in cohort 1 (80.6%, 95% CI: 64.0–91.8) and 10 of 21 patients in cohort 2 (47.6%, 95% CI: 25.7–70.2) achieved objective intracranial response by ICR. Hypercholesterolemia (92.7%) and hypertriglyceridemia (90.8%) (cluster terms) were common treatment-related adverse events (TRAEs). Nine patients (8.3%) had serious TRAEs; one permanently discontinued from treatment because of TRAEs.

      Conclusions

      Lorlatinib was found to have a robust and durable response and high intracranial objective response in previously treated Chinese patients with ALK-positive NSCLC.

      Keywords

      Introduction

      In NSCLC, rearrangements of the ALK gene occur in 2.7% to 7.5% of the cases.
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      EML4-ALK rearrangement in non-small cell lung cancer and non-tumor lung tissues.
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      • Bartolotti M.
      • et al.
      Anaplastic lymphoma kinase as a new target for the treatment of non-small-cell lung cancer.
      Such rearrangements lead to high sensitivity for ALK tyrosine kinase inhibitors (TKIs).
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      • Aisner D.L.
      • et al.
      Updated molecular testing guideline for the selection of lung cancer patients for treatment with targeted tyrosine kinase inhibitors: guideline from the College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology.
      Crizotinib, the first ALK TKI approved for treatment of advanced ALK-positive NSCLC, was established as first-line therapy.
      • Solomon B.
      • Soria J.C.
      The continuum of care for ALK-positive NSCLC: from diagnosis to new treatment options - an overview.
      Subsequently, several second-generation ALK inhibitors revealed to have superior efficacy to crizotinib were introduced as standard first-line treatments.
      • Planchard D.
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      • et al.
      Metastatic non-small cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.
      However, the potency and robust antitumor activity of these ALK TKIs are overshadowed by the persisting issue of development of drug resistance and progressive disease, often including central nervous system (CNS) metastases.
      • Gainor J.F.
      • Dardaei L.
      • Yoda S.
      • et al.
      Molecular mechanisms of resistance to first- and second-generation ALK inhibitors in ALK-rearranged lung cancer.
      ,
      • Ali A.
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      Survival of patients with non-small-cell lung cancer after a diagnosis of brain metastases.
      Lorlatinib is a selective, third-generation ALK and ROS1 TKI for the treatment of patients with ALK-positive metastatic NSCLC, with broader coverage against known ALK resistance mutations than both crizotinib and second-generation ALK TKIs and good CNS penetration.
      • Bauer T.M.
      • Shaw A.T.
      • Johnson M.L.
      • et al.
      Brain penetration of lorlatinib: cumulative incidences of CNS and non-CNS progression with lorlatinib in patients with previously treated ALK-positive non-small-cell lung cancer.
      ,
      • Shaw A.T.
      • Solomon B.J.
      • Besse B.
      • et al.
      ALK resistance mutations and efficacy of lorlatinib in advanced anaplastic lymphoma kinase-positive non-small-cell lung cancer.
      In a global phase 1 and 2 study (NCT01970865), lorlatinib reached its primary end point of confirmed objective response in treatment-naive patients or those who had progressed on crizotinib, a second-generation ALK TKI, or up to three ALK TKIs.
      • Solomon B.J.
      • Besse B.
      • Bauer T.M.
      • et al.
      Lorlatinib in patients with ALK-positive non-small-cell lung cancer: results from a global phase 2 study.
      Lorlatinib was also found to have robust overall and intracranial (IC) activities. In patients treated with at least one previous ALK TKI with or without chemotherapy, objective responses were achieved in 93 of 198 patients (47.0%, 95% confidence interval [CI]: 39.9–54.2), and IC-objective responses were achieved in 51 of 81 patients with measurable CNS lesions at baseline (63.0%, 95% CI: 51.5–73.4). Objective response was achieved in 41 of 59 patients who had only received previous crizotinib with or without chemotherapy (69.5%, 95% CI: 56.1–80.8), nine of 28 patients who had received one previous non-crizotinib ALK TKI with or without chemotherapy (32.1%, 95% CI: 15.9–52.4), and 43 of 111 patients who had received two or more previous ALK TKIs with or without chemotherapy (38.7%, 95% CI: 29.6–48.5). In addition, an IC objective response was achieved in 20 of 23 patients with measurable CNS lesions at baseline in patients who had only received previous crizotinib with or without chemotherapy (87.0%, 95% CI: 66.4–97.2), five of nine patients who had received one previous non-crizotinib ALK TKI with or without chemotherapy (55.6%, 95% CI: 21.2–86.3), and 26 of 49 patients who had received two or more ALK TKIs with or without chemotherapy (53.1%, 95% CI: 38.3–67.5).
      The global phase 1 and 2 study did not include patients from mainland China; therefore, more data are needed to evaluate the efficacy and safety of lorlatinib in the Chinese population. In the People’s Republic of China, crizotinib was approved in 2013 to treat patients with ALK-positive advanced NSCLC and has been established as the standard of care. Lorlatinib is currently not approved in the People’s Republic of China.
      Here, we report primary data from an ongoing phase 2, open-label, dual-cohort study of lorlatinib in patients with ALK-positive advanced or metastatic NSCLC from the People’s Republic of China who had progressed after treatment with crizotinib or another ALK TKI, with or without prior crizotinib.

      Materials and Methods

      Patients

      In this phase 2, open-label study (NCT03909971), eligible patients had ALK-positive advanced or metastatic NSCLC with progressive disease after treatment with an ALK TKI, at least one measurable extracranial target lesion (according to the Response Evaluation Criteria in Solid Tumors [RECIST] version 1.1) that had not been previously irradiated, an Eastern Cooperative Oncology Group performance status of 0 to 2, and adequate bone marrow, renal, pancreatic, and liver functions.

      Study Design

      Patients were included in one of the following two cohorts: cohort 1 included patients with progressive disease after crizotinib as the only prior ALK TKI and cohort 2 included patients with progressive disease after one ALK TKI other than crizotinib, with or without prior crizotinib. All patients received open-label, oral lorlatinib 100 mg daily (4 × 25 mg) in a continuous 3-week (21 d) cycle. Additional details can be found in the Supplementary Materials.
      The protocol was approved by the independent ethics committee at each site and complied with the International Ethical Guidelines for Biomedical Research Involving Human Subjects, Good Clinical Practice guidelines, the Declaration of Helsinki, and local laws. All patients provided written informed consent before any study activities.

      End Points

      The primary end point was objective response in cohort 1 according to the RECIST version 1.1 by independent central radiology (ICR) assessment, defined as a confirmed complete response or partial response recorded from enrollment to disease progression or start of new anticancer therapy.
      Secondary end points assessed in both cohorts per ICR and investigator included the following: objective response in cohort 2; duration of response (DoR), IC objective response, and IC-DoR; time to tumor response (TTR); and progression-free survival (PFS). Other secondary end points included objective response in cohort 1 per investigator assessment, overall survival (OS), and safety. These end points are defined in the Supplementary Methods.
      Posthoc exploratory analyses were also conducted for the following end points: PFS per ICR in patients with brain metastases at baseline; IC-PFS per ICR in patients with brain metastases at baseline; IC time to progression (TTP); objective response rate (ORR) for each ALK TKI other than crizotinib in cohort 2; and PFS per ICR in patients who received prior alectinib and in those who received prior alectinib or ceritinib. These end points are defined in the Supplementary Methods.
      In addition, single- and multiple-dose lorlatinib pharmacokinetic (PK) profiles were evaluated in patients undergoing intensive and sparse PK sampling for the following parameters: maximum plasma concentration (Cmax); time at which Cmax occurred (Tmax); area under the concentration-time profile from time zero to time tau (τ), the dosing interval, where tau = 24 hours (daily dosing, AUCtau) (at steady state), apparent clearance; and observed accumulation ratio (Rac). Further details are provided in the Supplementary Materials.

      Assessments

      Efficacy assessments were based on RECIST version 1.1 guidelines.
      • Eisenhauer E.A.
      • Therasse P.
      • Bogaerts J.
      • et al.
      New response evaluation criteria in solid tumours: revised RECIST guideline (version1.1).
      Modified RECIST 1.1 guidelines were used for the assessment of response of measurable IC disease. The schedule of assessments is provided in the Supplementary Materials.
      The assessment of adverse events (AEs) included AE type, incidence, severity (graded by the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03), timing, seriousness, and relation to treatment. Additional safety assessments included laboratory abnormalities, electrocardiography, left ventricular ejection fraction, and CNS effects.
      Blood samples for single and multiple PK profiling were evaluated by means of intensive PK sampling at time 0 (predose) and at 0.5 hour, 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 9 hours, and 24 hours on days 1 and 15 of cycle 1 in 16 patients. Steady-state PK exposure was evaluated by means of sparse PK sampling predose and 1 hour to 2 hours postdose on day 1 of cycles 2 to 5 in all patients.

      Statistical Analysis

      All efficacy and safety analyses were performed by cohort on patients who received at least one dose of the study drug. A historical control of 30% for ORR was chosen (based on the range of ORR of chemotherapy after previous systemic treatment or in patients with no prior treatment
      • Shaw A.T.
      • Kim D.W.
      • Nakagawa K.
      • et al.
      Crizotinib versus chemotherapy in advanced ALK-positive lung cancer.
      • Shaw A.T.
      • Kim T.M.
      • Crinò L.
      • et al.
      Ceritinib versus chemotherapy in patients with ALK-rearranged non-small-cell lung cancer previously given chemotherapy and crizotinib (ASCEND-5): a randomised, controlled, open-label, phase 3 trial.
      • Soria J.C.
      • Tan D.S.W.
      • Chiari R.
      • et al.
      First-line ceritinib versus platinum-based chemotherapy in advanced ALK-rearranged non-small-cell lung cancer (ASCEND-4): a randomised, open-label, phase 3 study.
      ) for cohort 1. It was assumed that there would be at least a 20% increase in ORR as a result of lorlatinib treatment; hence, 66 patients were required to provide 90% power to reject an ORR less than or equal to 30% with a one-sided 0.025 significance level based on a Fleming single-stage design. Because there was no established standard of care for patients enrolled in cohort 2 at the time the protocol was designed, this analysis was exploratory with a planned sample size of 34 patients to provide an estimated ORR with a maximum width of the 95% CI of 35%, observed with 17 responses from 34 patients.
      All 95% CIs for ORR and IC objective response were calculated using the Clopper–Pearson method. Median time to event and rate defined at clinical meaningful time points for DoR, IC-DoR, PFS, OS, IC-PFS, and IC-TTP were estimated using the Kaplan–Meier method, the corresponding 95% CIs for median were estimated using the Brookmeyer and Crowley method, and the CIs for DoR, IC-DoR, PFS, OS, IC-PFS, and IC-TTP estimates at defined clinical meaningful time points were derived using the log(–log) method according to Kalbfleisch and Prentice. TTR was reported using summary statistics.
      PK evaluation (steady-state lorlatinib PK exposure) was conducted in all patients having sparse PK sampling. PK parameters were summarized by day of assessment, including median, SD, and coefficient of variation to characterize lorlatinib’s PK profile. Box-whisker plots of trough concentrations by cycle and day were generated to assess the attainment and maintenance of PK steady state.

      Results

      Study Population

      In total, 109 patients were enrolled: 67 in cohort 1 and 42 in cohort 2. At the time of data cutoff (August 10, 2020), 32 patients (29.4%) had discontinued lorlatinib during the treatment period and 17 patients (15.6%) discontinued from the study because of death during the follow-up period (Supplementary Table 1).
      Patient demographics, disease characteristics, and prior anticancer therapy are summarized in Table 1. All patients were Chinese; 56 (51.4%) were female and 53 (48.6%) were male. The median (range) age was 51.0 (19–77) years. In cohort 1, there were four patients (6.0%) with stage IIIB cancer, one (1.5%) with stage IIIC cancer, and 62 (92.5%) with stage IV cancer. In cohort 2, all patients had stage IV cancer (n = 42; 100%). Crizotinib and ceritinib were the most frequently reported prior anticancer therapies.
      Table 1Patient Demographics, Disease Characteristics, and Prior Anticancer Therapy
      CharacteristicsCohort 1 (n = 67)Cohort 2 (n = 42)Total (N = 109)
      Demographics and disease characteristics
      Median age, y (range)50.0 (25–75)53.5 (19–77)51.0 (19–77)
      Median weight, kg (range)64.0 (39–105)62.3 (42–92)64.0 (39–105)
      ECOG performance status, n (%)
       08 (11.9)7 (16.7)15 (13.8)
       157 (85.1)32 (76.2)89 (81.7)
       22 (3.0)3 (7.1)5 (4.6)
      Measurable disease at baseline per ICR, n (%)57 (85.1)37 (88.1)94 (86.2)
      At least one intracranial lesion at baseline per ICR, n (%)36 (53.7)21 (50.0)57 (52.3)
      Smoking status, n (%)
       Never smoker44 (65.7)25 (59.5)69 (63.3)
       Former smoker23 (34.3)17 (40.5)40 (36.7)
      Histopathology (NSCLC), n (%)
       Adenocarcinoma56 (83.6)30 (71.4)86 (68.8)
       Adenosquamous carcinoma9 (13.4)10 (23.8)19 (17.4)
       Squamous cell carcinoma02 (4.8)2 (1.8)
       Large cell carcinoma1 (1.5)01 (0.9)
       Unknown1 (1.5)01 (0.9)
      Prior anticancer therapy
      Patients with at least one prior ALK inhibitor, n (%)67 (100.0)42 (100.0)109 (100.0)
       Only crizotinib67 (100.0)067 (61.5)
       Crizotinib plus non-crizotinib ALK inhibitor026 (61.9)26 (23.9)
      Crizotinib026 (61.9)26 (23.9)
      Ceritinib010 (23.8)10 (9.2)
      Alectinib09 (21.4)9 (8.3)
      Brigatinib03 (7.1)3 (2.8)
      Ensartinib03 (7.1)3 (2.8)
      Other (investigational drug)02 (4.8)2 (1.8)
       Only non-crizotinib ALK inhibitor016 (38.1)16 (14.7)
      Alectinib09 (21.4)9 (8.3)
      Ceritinib01 (2.4)1 (0.9)
      Ensartinib03 (7.1)3 (2.8)
      Other (investigational drug)03 (7.1)3 (2.8)
      Prior chemotherapy for metastatic or advanced disease16 (23.9)16 (38.1)32 (29.4)
      ECOG, Eastern Cooperative Oncology Group; ICR, independent central radiology.

      Efficacy

      This study met the primary objective; the confirmed ORR per ICR assessment in cohort 1 was 70.1% (95% CI: 57.7–80.7), which was determined to have clinically meaningful and statistically significant improvement compared with the historical control (p < 0.0001) (Table 2). Furthermore, eight patients (11.9%) achieved complete response, 39 (58.2%) achieved partial response, and eight (11.9%) achieved stable disease (Table 2 and Fig. 1).
      Table 2Summary of Objective Response and IC Objective Response per ICR
      ResponseCohort 1 (n = 67)Cohort 2 (n = 42)
      Confirmed best overall response, n (%)
       Complete response8 (11.9)2 (4.8)
       Partial response39 (58.2)18 (42.9)
       Stable disease8 (11.9)6 (14.3)
       Non-complete response/non-progressive disease7 (10.4)3 (7.1)
       Progressive disease4 (6.0)10 (23.8)
       Not evaluated1 (1.5)3 (7.1)
      Objective response (complete response + partial response), n (%)47 (70.1)20 (47.6)
       95% CI
      The Clopper–Pearson method was used.
      57.7–80.732.0–63.6
      p value
      One-sided p value based on exact test for null hypothesis ORR ≤ 30%.
      <0.0001
      DoR
      In patients with confirmed objective response.
       Median, mo (95% CI)NR (9.7–NR)11.2 (2.9–NR)
       <6 mo, n (%)11 (23.4)10 (50.0)
       ≥6 to <9 mo, n (%)22 (46.8)5 (25.0)
       ≥9 to <12 mo, n (%)14 (29.8)4 (20.0)
      TTR
      In patients with confirmed objective response.
       Median, mo (range)1.4 (0.6–11.1)1.4 (1.2–5.6)
      Intracranial response
      Only included patients for whom the brain lesions had been chosen as RECIST target or non-target lesions at baseline.
      Cohort 1 (n = 36)Cohort 2 (n = 21)
      Confirmed best overall response, n (%)
       Complete response19 (52.8)6 (28.6)
       Partial response10 (27.8)4 (19.0)
       Stable disease02 (9.5)
       Non-complete response/non-progressive disease2 (5.6)3 (14.3)
       Progressive disease3 (8.3)6 (28.6)
       Not evaluated2 (5.6)0
      IC objective response (complete response + partial response), n (%)29 (80.6)10 (47.6)
       95% CI
      The Clopper–Pearson method was used.
      64.0–91.825.7–70.2
      DoR
      Only included patients with confirmed IC objective response.
       Median, mo (95% CI)NR (NR–NR)NR (5.6–NR)
       <6 mo, n (%)4 (13.8)5 (50.0)
       ≥6 to <9 mo, n (%)8 (27.6)3 (30.0)
       ≥9 to <12 mo, n (%)16 (55.2)2 (20.0)
       ≥12 to <15 mo, n (%)1 (3.4)0
      CI, confidence interval; DoR, duration of response; IC, intracranial; ICR, independent central radiology; NR, not reached; ORR, objective response rate; RECIST, Response Evaluation Criteria in Solid Tumors; TTR, time to response.
      a The Clopper–Pearson method was used.
      b One-sided p value based on exact test for null hypothesis ORR ≤ 30%.
      c In patients with confirmed objective response.
      d Only included patients for whom the brain lesions had been chosen as RECIST target or non-target lesions at baseline.
      e Only included patients with confirmed IC objective response.
      Figure thumbnail gr1
      Figure 1Best percent change from baseline in sum of diameters for target lesions per ICR assessment in (A) cohort 1 and (B) cohort 2 (patients with target lesions).

      Secondary and Posthoc End Points

      Efficacy results per ICR assessment are described herein; efficacy results per investigator assessment are presented in the Supplementary Materials (Supplementary Results and Supplementary Table 2). In cohort 2, the confirmed ORR per ICR was 47.6% (95% CI: 32.0–63.6; Table 2). Two patients (4.8%) in cohort 2 achieved complete response, 18 (42.9%) achieved partial response, and six (14.3%) achieved stable disease. In addition, based on the posthoc analysis, objective response was achieved in nine (50.0%; 95% CI: 26.0–74.0) of 18 patients who received prior alectinib; five (45.5%; 95% CI: 16.7–76.6) of 11 who received prior ceritinib; two (33.3%; 95% CI: 4.2–77.7) of six who received prior ensartinib; two (100.0%; 95% CI: 15.8–100) of two who received prior brigatinib; and two (40.0%; 95% CI: 5.3–85.3) of five who received prior investigational ALK TKI (Supplementary Table 3).
      Median DoR for patients with a confirmed objective response was not reached (NR) (95% CI: 9.7–NR) in cohort 1 (Table 2) and was 11.2 months (95% CI: 2.9–NR) in cohort 2.
      Median TTR in patients with confirmed objective response was 1.4 months (range: 0.6–11.1) in cohort 1 (Table 2) and 1.4 months (range: 1.2–5.6) in cohort 2.
      The median time of follow-up for PFS was 11.0 months (95% CI: 9.7–11.1) for cohort 1 and 9.7 months (95% CI: 8.2–12.4) for cohort 2. PFS data were immature in cohort 1, and median PFS was NR (95% CI: NR–NR) (Fig. 2); the probability of being event-free at 12 months was 66.4% (95% CI: 52.4–77.1). In cohort 2, median PFS was 5.6 months (95% CI: 2.9–9.7); the probability of being event-free at 12 months was 34.2% (95% CI: 19.2–49.8). In addition, based on the posthoc analysis, median PFS in 18 patients who received prior alectinib was 6.2 months (95% CI: 2.7–NR), and median PFS in 29 patients who received prior alectinib or ceritinib was 5.4 months (95% CI: 2.7–7.4) (Supplementary Table 4).
      Figure thumbnail gr2
      Figure 2Kaplan–Meier plot of PFS per ICR assessment. CI, confidence interval; ICR, independent central review; NR, not reached; PFS, progression-free survival.
      In patients with brain metastases at baseline in cohort 1, median PFS per ICR assessment was NR (95% CI: NR–NR) (Supplementary Table 5); the probability of being event-free at 12 months was 72.7% (95% CI: 53.7–84.9). In cohort 2, median PFS per ICR assessment was 4.8 months (95% CI: 2.7–9.7); the probability of being event-free at 12 months was 20.0% (95% CI: 4.6–43.1).
      As a large proportion of patients had their OS data censored and few patients had died by the cutoff date, OS data were immature. Median duration of follow-up for OS was 11.5 months (95% CI: 11.0–11.9) in cohort 1 and 12.2 months (95% CI: 11.0–12.8) in cohort 2. In cohort 1, three (4.5%) patients were known to have died, and the median OS was NR (95% CI: NR–NR). In cohort 2, 14 (33.3%) patients were known to have died, and the median OS was NR (95% CI: 10.3–NR).

      IC Efficacy

      IC efficacy results per ICR assessment are described herein; IC efficacy results per investigator assessment are presented in the Supplementary Materials (Supplementary Results and Supplementary Table 2). IC-ORR per ICR was achieved in 29 of 36 patients (80.6%; 95% CI: 64.0–91.8) in cohort 1 and 10 of 21 patients (47.6%; 95% CI: 25.7–70.2) in cohort 2 among those with baseline measurable or unmeasurable CNS lesions (Table 2).
      IC-ORR per ICR was achieved in 14 of 15 patients (93.3%; 95% CI: 68.1–99.8) in cohort 1 and five of 12 patients (41.7%; 95% CI: 15.2–72.3) in cohort 2 among patients with baseline measurable CNS lesions.
      Median IC-DoR among patients with a confirmed IC objective response per ICR was NR (95% CI: 9.7–NR) in cohort 1 and NR (95% CI: NR–NR) in cohort 2 among patients with baseline measurable or unmeasurable CNS lesions.
      In patients with or without brain metastases at baseline in cohort 1, median IC-TTP per ICR assessment was NR (95% CI: NR–NR); the probability of being event-free at 12 months was 80.7% (95% CI: 65.0–89.9) (Supplementary Table 6). Median IC-TTP per ICR assessment in cohort 2 was NR (95% CI: 2.9–NR); the probability of being event-free at 12 months was 52.2% (95% CI: 27.4–72.1).
      In patients with brain metastases at baseline in cohort 1, median IC-PFS per ICR assessment was NR (95% CI: NR–NR) (Supplementary Table 7); the probability of being event-free at 12 months was 85.0% (95% CI: 67.4–93.5). In cohort 2, median IC-PFS per ICR assessment was NR (95% CI: 2.7–NR); the probability of being event-free at 12 months was 51.6% (95% CI: 26.3–72.0). In patients with brain metastases at baseline in cohort 1, median IC-TTP per ICR assessment was NR (95% CI: NR–NR); the probability of being event-free at 12 months was 85.0% (95% CI: 67.4–93.5) (Supplementary Table 8). Median IC-TTP per ICR assessment in cohort 2 was NR (95% CI: 2.7–NR); the probability of being event-free at 12 months was 51.6% (95% CI: 26.3–72.0).

      Safety

      Median exposure to treatment was 11.4 months (range: 1.4–14.9) in cohort 1 and 8.43 months (range: 0.7–14.9) in cohort 2. The median relative dose intensity was 99.72% (range: 54.1–100) in cohort 1 and 99.85% (range: 68.6–100) in cohort 2. All patients reported at least one AE (Supplementary Table 9). When appropriate, AEs were manageable through dose interruption, dose reduction, or standard supportive medical therapy. Most grade 3 or 4 all-causality AEs (reported in 54.1% of the patients) were most frequently associated with laboratory abnormalities. Three patients (2.8%) permanently withdrew from treatment because of AEs (all-causality). All-causality grade 5 AEs were reported in eight (7.3%) patients (one patient with neoplasm progression in cohort 1 and seven patients with pneumonia [n = 3], respiratory failure [n = 1], death [n = 2], sudden death [n = 1], and lung neoplasm malignant [n = 1] in cohort 2). None of these AEs were considered treatment related by the investigator.
      Among the 109 patients in both cohorts, the most frequently reported (≥20% patients) treatment-related AEs (TRAEs) by decreasing frequency of patients were hypercholesterolemia (cluster term) (n = 101, 92.7%), hypertriglyceridemia (cluster term) (n = 99, 90.8%), increased alanine aminotransferase (n = 47, 43.1%), increased aspartate aminotransferase (n = 44, 40.4%), increased weight (n = 35, 32.1%), edema (cluster term) (n = 29, 26.6%), and increased gamma-glutamyl transferase (n = 26, 23.9%) (Table 3).
      Table 3Most Frequent Treatment-Related AEs Occurring in Greater Than or Equal to 10% of Patients in Either Cohort
      Adverse eventTotal (N = 109)
      All grades, n (%)Grade 3, n (%)Grade 4, n (%)
      Patients with any AE107 (98.2)33 (30.3)15 (13.8)
      Hypercholesterolemia
      Cluster term.
      101 (92.7)11 (10.1)2 (1.8)
      Hypertriglyceridemia
      Cluster term.
      99 (90.8)19 (17.4)11 (10.1)
      Increased ALT47 (43.1)2 (1.8)0
      Increased AST44 (40.4)3 (2.8)0
      Increased weight35 (32.1)7 (6.4)0
      Edema
      Cluster term.
      29 (26.6)1 (0.9)0
      Increased GGT26 (23.9)2 (1.8)0
      Increased LDL21 (19.3)00
      Prolonged QT18 (16.5)00
      Hyperglycemia18 (16.5)3 (2.8)0
      Anemia17 (15.6)1 (0.9)0
      Peripheral neuropathy
      Cluster term.
      12 (11.0)00
      Note: Patients were only counted once per cohort per event.
      AE, adverse event; ALT, alanine aminotransferase; AST, aspartate aminotransferase; GGT, gamma-glutamyl transferase; LDL, low-density lipoprotein.
      a Cluster term.
      The number of patients with CNS AEs was low overall, with a total of seven patients (6.4%) reporting a CNS AE. Three (2.8%) reported cognitive effects (cluster term), two (1.8%) mood effects (cluster term), one (0.9%) speech effects (cluster term), and one patient (0.9%) reported two episodes of psychotic effects (cluster term). Most CNS AEs were treatment related, with except for speech effects. Most patients (five of seven) reporting CNS-related AEs had brain metastases at baseline, and of those patients, two had received prior radiation therapy to the brain. Most CNS AEs were grade 1 or 2, and no patient discontinued treatment because of a CNS AE. Five patients had no dose modification of lorlatinib or concomitant medication prescribed; of those, two AEs resolved, one was improved, and two were not resolved at the data cutoff date. One case of a grade 3 cognitive effects AE was resolved after dose reduction. One grade 1 psychotic effect AE was managed with concomitant medication without dosage alterations, and one grade 2 psychotic effect AE was managed with dose modification and concomitant medication and was resolved.

      Pharmacokinetics

      In the assessed two cohorts of 16 patients (8 patients in cohort 1, 8 patients in cohort 2), absorption after a single oral dose (100 mg) of lorlatinib was rapid with median Tmax of 1.02 hours on day 1. The observed geometric mean of AUCtau was 7540 ng × h/mL and Cmax was 1038 ng/mL. Exposures as measured by AUCtau and Cmax were comparable between cohort 1 and cohort 2 (Supplementary Table 10). Cmax was reached after multiple doses on cycle 1 day 15, with a median Tmax of 1.88 hours. The observed geometric mean of AUCtau was 6007 ng × h/mL and Cmax was 710.8 ng/mL, suggesting an overall autoinduction of drug-metabolizing enzymes. The geometric mean apparent clearance was 16.65 liter/h and the Rac for AUCtau was 0.8330. Exposures as measured by AUCtau and Cmax were slightly higher in cohort 2 compared with cohort 1 (Supplementary Table 10). Between-participant variability in plasma lorlatinib exposure on days 1 and 15 based on geometric coefficient of variability ranged from 42% to 58% for Cmax and from 17% to 40% for AUCtau. Steady-state lorlatinib plasma concentration seemed to be reached by day 15, as evidenced by similar trough and peak concentrations of lorlatinib observed on PK collection days on and after cycle 1 day 15 up to cycle 5. The mean plasma trough concentration among all patients after steady-state attainment was 124.18 ng/mL. There was no evidence for substantial changes in lorlatinib PK with long-term dosing of 100 mg daily after steady state was reached (Supplementary Fig. 1).

      Discussion

      Here, we report the first analysis of lorlatinib efficacy in Chinese patients with locally advanced or metastatic ALK-positive NSCLC whose disease had progressed after crizotinib treatment (cohort 1) or whose disease had progressed after ALK inhibitor treatment other than crizotinib, with or without prior crizotinib (cohort 2). Patients treated with lorlatinib had a clinically meaningful and statistically significant improvement compared with historical controls (p < 0.0001) in ORR per ICR in cohort 1 (the primary end point) and a clinically meaningful improvement in ORR in cohort 2.
      The rapid and durable antitumor responses observed in both cohorts were consistent with the efficacy results of the prior global phase 2 study,
      • Solomon B.J.
      • Besse B.
      • Bauer T.M.
      • et al.
      Lorlatinib in patients with ALK-positive non-small-cell lung cancer: results from a global phase 2 study.
      suggesting Chinese patients achieve similar clinical benefit with lorlatinib as the global population (ORR per ICR for this Chinese population: cohort 1, 70.1% [95% CI: 57.7–80.7], similar global population 69.5% [95% CI: 56.1–80.8]; cohort 2, 47.6% [95% CI: 32.0–63.6], similar global population 32.1% [95% CI: 15.9–52.4]). In addition, the ORR per ICR reported here for Chinese patients treated with lorlatinib after prior alectinib, ceritinib, or brigatinib was consistent with that reported in the global phase 2 population.
      • Solomon B.J.
      • Besse B.
      • Bauer T.M.
      • et al.
      Lorlatinib in patients with ALK-positive non-small-cell lung cancer: results from a global phase 2 study.
      Nevertheless, patient numbers in these groups were low in this study, limiting interpretation.
      This first demonstration of the efficacy of lorlatinib for Chinese patients is particularly important given that lung cancer was the leading cause of cancer death in the People's Republic of China in 2020. The observed results might be expected given that the proportion of lung adenocarcinoma cases with ALK fusions (5.1%) in China
      • Pan Y.
      • Zhang Y.
      • Li Y.
      • et al.
      ALK, ROS1 and RET fusions in 1139 lung adenocarcinomas: a comprehensive study of common and fusion pattern-specific clinicopathologic, histologic and cytologic features.
      is similar to that in the global patient population.
      • Sasaki T.
      • Rodig S.J.
      • Chirieac L.R.
      • Jänne P.A.
      The biology and treatment of EML4-ALK non-small cell lung cancer.
      This study revealed the clinical benefit of lorlatinib in patients who received one or more prior ALK TKI and is the first to reveal the clinical benefit of lorlatinib in Chinese patients who received prior ALK TKIs other than crizotinib, although patient numbers were limited.
      CNS metastases are estimated to occur in 20% to 30% of ALK TKI treatment-naive patients with ALK-positive NSCLC
      • Toyokawa G.
      • Seto T.
      • Takenoyama M.
      • Ichinose Y.
      Insights into brain metastasis in patients with ALK+ lung cancer: is the brain truly a sanctuary?.
      and are in more than 60% of patients previously treated with an ALK TKI.
      • Bauer T.M.
      • Shaw A.T.
      • Johnson M.L.
      • et al.
      Brain penetration of lorlatinib: cumulative incidences of CNS and non-CNS progression with lorlatinib in patients with previously treated ALK-positive non-small-cell lung cancer.
      CNS metastases are linked to poor prognosis
      • Bauer T.M.
      • Shaw A.T.
      • Johnson M.L.
      • et al.
      Brain penetration of lorlatinib: cumulative incidences of CNS and non-CNS progression with lorlatinib in patients with previously treated ALK-positive non-small-cell lung cancer.
      ; in addition, the CNS is a common site of progressive disease during treatment, representing a major clinical issue.
      • Ali A.
      • Goffin J.R.
      • Arnold A.
      • Ellis P.M.
      Survival of patients with non-small-cell lung cancer after a diagnosis of brain metastases.
      Lorlatinib was found to have substantial IC activity independent of potential measurable or nonmeasurable brain metastases at baseline and regardless of prior treatment, both in the global study
      • Bauer T.M.
      • Shaw A.T.
      • Johnson M.L.
      • et al.
      Brain penetration of lorlatinib: cumulative incidences of CNS and non-CNS progression with lorlatinib in patients with previously treated ALK-positive non-small-cell lung cancer.
      ,
      • Solomon B.J.
      • Besse B.
      • Bauer T.M.
      • et al.
      Lorlatinib in patients with ALK-positive non-small-cell lung cancer: results from a global phase 2 study.
      and in this study of Chinese patients, consistent with the ability of lorlatinib to cross the blood–brain barrier found in preclinical models.
      • Collier T.L.
      • Maresca K.P.
      • Normandin M.D.
      • et al.
      Brain penetration of the ROS1/ALK inhibitor lorlatinib confirmed by PET.
      ,
      • Collier T.L.
      • Normandin M.D.
      • Stephenson N.A.
      • et al.
      Synthesis and preliminary PET imaging of 11C and 18F isotopologues of the ROS1/ALK inhibitor lorlatinib.
      IC-ORR per ICR for patients with any brain metastases at baseline in cohort 1 (80.6, 95% CI: 64.0–91.8) was similar to the corresponding global study’s pooled cohort (87.5%, 95% CI: 67.6–97.3).
      • Bauer T.M.
      • Shaw A.T.
      • Johnson M.L.
      • et al.
      Brain penetration of lorlatinib: cumulative incidences of CNS and non-CNS progression with lorlatinib in patients with previously treated ALK-positive non-small-cell lung cancer.
      In cohort 2, the IC-ORR per ICR (47.6%, 95% CI: 25.7–70.2) corresponded with the global study’s respective pooled cohort (54.4%, 95% CI: 40.7–67.6). In addition to the effects of lorlatinib in treating brain metastases, lorlatinib may also be particularly effective in preventing CNS progression based on findings from a global first-line study
      • Shaw A.T.
      • Bauer T.M.
      • de Marinis F.
      • et al.
      First-line lorlatinib or crizotinib in advanced ALK-positive lung cancer.
      and in late-line–treated Chinese patients. In Chinese patients with brain metastases at baseline, IC-PFS was NR in both cohort 1 or cohort 2.
      The safety results from this study were generally consistent with the findings of the global phase 2 study,
      • Solomon B.J.
      • Besse B.
      • Bauer T.M.
      • et al.
      Lorlatinib in patients with ALK-positive non-small-cell lung cancer: results from a global phase 2 study.
      with a low number of discontinuations owing to AEs and no treatment-related deaths. Some of the most common grade 3 or 4 TRAEs (hypercholesterolemia [cluster term], hypertriglyceridemia [cluster term], increased alanine aminotransferase, and increased aspartate aminotransferase) are associated with laboratory abnormalities, which can be manageable through dose interruption, dose reduction, or standard supportive medical therapy.
      • Bauer T.M.
      • Felip E.
      • Solomon B.J.
      • et al.
      Clinical management of adverse events associated with lorlatinib.
      The frequency of patients with AEs related to the CNS (cluster terms of mood effects, cognitive effects, psychotic effects, and speech effects) was overall low (6.4%) in this study and lower than in the global phase 2 study, which reported CNS effects of any cause in 107 of 275 patients (39%).
      • Solomon B.J.
      • Besse B.
      • Bauer T.M.
      • et al.
      Lorlatinib in patients with ALK-positive non-small-cell lung cancer: results from a global phase 2 study.
      This could be due to the younger population in this study; 65.1% of the participants were 45 to less than 65 years, and 11.9% were more than or equal to 65 years (median = 51.0 y), compared with a median age of 54.0 years in the global study. CNS-related events were generally mild to moderate with only one grade 3 AE (cognitive effect) and no patient discontinuing treatment because of a CNS AE. For some of the most common TRAEs, edema (cluster term) (26.6%) and peripheral neuropathy (cluster term) (11.0%), the frequency (any grade) was lower in this study compared with the lorlatinib phase 2 global study (edema 43%, peripheral neuropathy 30%).
      • Solomon B.J.
      • Besse B.
      • Bauer T.M.
      • et al.
      Lorlatinib in patients with ALK-positive non-small-cell lung cancer: results from a global phase 2 study.
      This could also be due to the younger population in this study; further follow-up is warranted. The frequency of patients with liver-related AEs is higher in this study compared with lorlatinib global studies.
      • Solomon B.J.
      • Besse B.
      • Bauer T.M.
      • et al.
      Lorlatinib in patients with ALK-positive non-small-cell lung cancer: results from a global phase 2 study.
      ,
      • Shaw A.T.
      • Bauer T.M.
      • de Marinis F.
      • et al.
      First-line lorlatinib or crizotinib in advanced ALK-positive lung cancer.
      This is common in other NSCLC clinical trials, including but not limited to ALK TKI studies.
      • Soria J.C.
      • Tan D.S.W.
      • Chiari R.
      • et al.
      First-line ceritinib versus platinum-based chemotherapy in advanced ALK-rearranged non-small-cell lung cancer (ASCEND-4): a randomised, open-label, phase 3 study.
      ,
      • Crinò L.
      • Ahn M.J.
      • De Marinis F.
      • et al.
      Multicenter phase II study of whole-body and intracranial activity with ceritinib in patients with ALK-rearranged non-small-cell lung cancer previously treated with chemotherapy and crizotinib: results from ASCEND-2.
      • Wu Y.L.
      • Cheng Y.
      • Zhou X.
      • et al.
      Dacomitinib versus gefitinib as first-line treatment for patients with EGFR-mutation-positive non-small-cell lung cancer (ARCHER 1050): a randomised, open-label, phase 3 trial.
      • Cheng Y.
      • Mok T.S.
      • Zhou X.
      • et al.
      Safety and efficacy of first-line dacomitinib in Asian patients with EGFR mutation-positive non-small cell lung cancer: results from a randomized, open-label, phase 3 trial (ARCHER 1050).
      PK data from both cohorts were generally consistent with the established PK profile for lorlatinib.
      • Chen J.
      • O’Gorman M.T.
      • James L.P.
      • Klamerus K.J.
      • Mugundu G.
      • Pithavala Y.K.
      Pharmacokinetics of lorlatinib after single and multiple dosing in patients with anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer: results from a global phase I/II study.
      Plasma concentration seemed to reach steady state by 15 days; the relatively stable trough plasma concentration indicated no considerable PK changes with long-term lorlatinib dosing.
      Data for both PFS (cohort 1) and OS were immature, as a large proportion of patients had PFS and OS data censored and few patients had objective progression or death at the cutoff date. Additional follow-up is needed to provide mature results. A recent global, randomized, phase 3 trial (NCT03052608) compared the efficacy of lorlatinib with crizotinib in 296 treatment-naive patients with ALK-positive NSCLC (including Chinese patients): at 12 months, 78% of the patients in the lorlatinib group were alive without progressive disease versus 39% in the crizotinib group.
      • Shaw A.T.
      • Bauer T.M.
      • de Marinis F.
      • et al.
      First-line lorlatinib or crizotinib in advanced ALK-positive lung cancer.
      Therefore, lorlatinib was found to have clinical benefit in first-line– and late-line–treated Chinese patients with ALK-positive NSCLC.
      Overall, this study confirms that the established clinical benefit of lorlatinib for previously treated advanced ALK-positive NSCLC extends to the Chinese patient population. Importantly, given that CNS metastases are common, lorlatinib was also associated with IC tumor responses, reflecting its CNS penetration. The safety profile was consistent with prior global studies and revealed that lorlatinib was well tolerated, with a low rate of discontinuation owing to AE and low rate of CNS AEs, a concern among patients and physicians. Further follow-up into the use of lorlatinib and potential biomarkers of resistance is warranted.

      CRediT Authorship Contribution Statement

      Shun Lu, Yi-Long Wu: Conceptualization, Data curation, Investigation, Writing - review & editing.
      Qing Zhou, Xiaoqing Liu, Yingying Du, Yun Fan, Ying Cheng, Jian Fang, You Lu, Cheng Huang, Jianying Zhou, Yong Song, Kai Wang, Hongming Pan, Nong Yang, Juan Li, Gongyan Chen, Jianhua Chang, Jiuwei Cui, Zhe Liu, Chunxue Bai, Helong Zhang: Data curation, Writing - review & editing.
      Huadong Zhao, Kaiting Zhang, Gerson Peltz, Heyan Li: Data curation, Formal analysis, Writing - review & editing.

      Data Sharing Statement

      On request and subject to review, Pfizer will provide the data that support the findings of this study. Subject to certain criteria, conditions, and exceptions, Pfizer may also provide access to the related individual de-identified participant data. See https://www.pfizer.com/science/clinical-trials/trial-data-and-results for more information.

      Acknowledgments

      This study was sponsored by Pfizer. The study sponsor was involved in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; and in the decision to submit the article for publication. The authors thank the participating patients and their families, the investigators, subinvestigators, research nurses, study coordinators, and operations staff. Editorial and medical writing support was provided by Marius Dettmer, PhD, of CMC AFFINITY, McCann Health Medical Communications, and was funded by Pfizer.

      Supplementary Data

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