Resensitization to Crizotinib by the Lorlatinib ALK Resistance Mutation L1198F.

In a patient who had metastatic anaplastic lymphoma kinase (ALK)-rearranged lung cancer, resistance to crizotinib developed because of a mutation in the ALK kinase domain. This mutation is predicted to result in a substitution of cysteine by tyrosine at amino acid residue 1156 (C1156Y). Her tumor did not respond to a second-generation ALK inhibitor, but it did respond to lorlatinib (PF-06463922), a third-generation inhibitor. When her tumor relapsed, sequencing of the resistant tumor revealed an ALK L1198F mutation in addition to the C1156Y mutation. The L1198F substitution confers resistance to lorlatinib through steric interference with drug binding. However, L1198F paradoxically enhances binding to crizotinib, negating the effect of C1156Y and resensitizing resistant cancers to crizotinib. The patient received crizotinib again, and her cancer-related symptoms and liver failure resolved. (Funded by Pfizer and others; ClinicalTrials.gov number, NCT01970865.).

Lorlatinib in patients with ALK-positive non-small-cell lung cancer: results from a global phase 2 study.

BACKGROUND: Lorlatinib is a potent, brain-penetrant, third-generation inhibitor of ALK and ROS1 tyrosine kinases with broad coverage of ALK mutations. In a phase 1 study, activity was seen in patients with ALK-positive non-small-cell lung cancer, most of whom had CNS metastases and progression after ALK-directed therapy. We aimed to analyse the overall and intracranial antitumour activity of lorlatinib in patients with ALK-positive, advanced non-small-cell lung cancer. METHODS: In this phase 2 study, patients with histologically or cytologically ALK-positive or ROS1-positive, advanced, non-small-cell lung cancer, with or without CNS metastases, with an Eastern Cooperative Oncology Group performance status of 0, 1, or 2, and adequate end-organ function were eligible. Patients were enrolled into six different expansion cohorts (EXP1-6) on the basis of ALK and ROS1 status and previous therapy, and were given lorlatinib 100 mg orally once daily continuously in 21-day cycles. The primary endpoint was overall and intracranial tumour response by independent central review, assessed in pooled subgroups of ALK-positive patients. Analyses of activity and safety were based on the safety analysis set (ie, all patients who received at least one dose of lorlatinib) as assessed by independent central review. Patients with measurable CNS metastases at baseline by independent central review were included in the intracranial activity analyses. In this report, we present lorlatinib activity data for the ALK-positive patients (EXP1-5 only), and safety data for all treated patients (EXP1-6). This study is ongoing and is registered with ClinicalTrials.gov, number NCT01970865. FINDINGS: Between Sept 15, 2015, and Oct 3, 2016, 276 patients were enrolled: 30 who were ALK positive and treatment naive (EXP1); 59 who were ALK positive and received previous crizotinib without (n=27; EXP2) or with (n=32; EXP3A) previous chemotherapy; 28 who were ALK positive and received one previous non-crizotinib ALK tyrosine kinase inhibitor, with or without chemotherapy (EXP3B); 112 who were ALK positive with two (n=66; EXP4) or three (n=46; EXP5) previous ALK tyrosine kinase inhibitors with or without chemotherapy; and 47 who were ROS1 positive with any previous treatment (EXP6). One patient in EXP4 died before receiving lorlatinib and was excluded from the safety analysis set. In treatment-naive patients (EXP1), an objective response was achieved in 27 (90·0%; 95% CI 73·5-97·9) of 30 patients. Three patients in EXP1 had measurable baseline CNS lesions per independent central review, and objective intracranial responses were observed in two (66·7%; 95% CI 9·4-99·2). In ALK-positive patients with at least one previous ALK tyrosine kinase inhibitor (EXP2-5), objective responses were achieved in 93 (47·0%; 39·9-54·2) of 198 patients and objective intracranial response in those with measurable baseline CNS lesions in 51 (63·0%; 51·5-73·4) of 81 patients. Objective response was achieved in 41 (69·5%; 95% CI 56·1-80·8) of 59 patients who had only received previous crizotinib (EXP2-3A), nine (32·1%; 15·9-52·4) of 28 patients with one previous non-crizotinib ALK tyrosine kinase inhibitor (EXP3B), and 43 (38·7%; 29·6-48·5) of 111 patients with two or more previous ALK tyrosine kinase inhibitors (EXP4-5). Objective intracranial response was achieved in 20 (87·0%; 95% CI 66·4-97·2) of 23 patients with measurable baseline CNS lesions in EXP2-3A, five (55·6%; 21·2-86·3) of nine patients in EXP3B, and 26 (53·1%; 38·3-67·5) of 49 patients in EXP4-5. The most common treatment-related adverse events across all patients were hypercholesterolaemia (224 [81%] of 275 patients overall and 43 [16%] grade 3-4) and hypertriglyceridaemia (166 [60%] overall and 43 [16%] grade 3-4). Serious treatment-related adverse events occurred in 19 (7%) of 275 patients and seven patients (3%) permanently discontinued treatment because of treatment-related adverse events. No treatment-related deaths were reported. INTERPRETATION: Consistent with its broad ALK mutational coverage and CNS penetration, lorlatinib showed substantial overall and intracranial activity both in treatment-naive patients with ALK-positive non-small-cell lung cancer, and in those who had progressed on crizotinib, second-generation ALK tyrosine kinase inhibitors, or after up to three previous ALK tyrosine kinase inhibitors. Thus, lorlatinib could represent an effective treatment option for patients with ALK-positive non-small-cell lung cancer in first-line or subsequent therapy. FUNDING: Pfizer.

Lorlatinib in non-small-cell lung cancer with ALK or ROS1 rearrangement: an international, multicentre, open-label, single-arm first-in-man phase 1 trial.

BACKGROUND: Most patients with anaplastic lymphoma kinase (ALK)-rearranged or ROS proto-oncogene 1 (ROS1)-rearranged non-small-cell lung cancer (NSCLC) are sensitive to tyrosine kinase inhibitor (TKI) therapy, but resistance invariably develops, commonly within the CNS. This study aimed to analyse the safety, efficacy, and pharmacokinetic properties of lorlatinib, a novel, highly potent, selective, and brain-penetrant ALK and ROS1 TKI with preclinical activity against most known resistance mutations, in patients with advanced ALK-positive or ROS1-positive NSCLC. METHODS: In this international multicentre, open-label, single-arm, first-in-man phase 1 dose-escalation study, eligible patients had advanced ALK-positive or ROS1-positive NSCLC and were older than 18 years, with an Eastern Cooperative Oncology Group performance status of 0 or 1, and adequate end-organ function. Lorlatinib was administered orally to patients at doses ranging from 10 mg to 200 mg once daily or 35 mg to 100 mg twice daily, with a minimum of three patients receiving each dose. For some patients, tumour biopsy was done before lorlatinib treatment to identify ALK resistance mutations. Safety was assessed in patients who received at least one dose of lorlatinib; efficacy was assessed in the intention-to-treat population (patients who received at least one dose of study treatment and had either ALK or ROS1 rearrangement). The primary endpoint was dose-limiting toxicities during cycle 1 according to investigator assessment; secondary endpoints included safety, pharmacokinetics, and overall response. This study is ongoing and is registered with ClinicalTrials.gov, number NCT01970865. FINDINGS: Between Jan 22, 2014, and July 10, 2015, 54 patients received at least one dose of lorlatinib, including 41 (77%) with ALK-positive and 12 (23%) with ROS1-positive NSCLC; one patient had unconfirmed ALK and ROS1 status. 28 (52%) patients had received two or more TKIs, and 39 (72%) patients had CNS metastases. The most common treatment-related adverse events among the 54 patients were hypercholesterolaemia (39 [72%] of 54 patients), hypertriglyceridaemia (21 [39%] of 54 patients), peripheral neuropathy (21 [39%] of 54 patients), and peripheral oedema (21 [39%] of 54 patients). One dose-limiting toxicity occurred at 200 mg (the patient did not take at least 16 of 21 prescribed total daily doses in cycle 1 because of toxicities attributable to study drug, which were grade 2 neurocognitive adverse events comprising slowed speech and mentation and word-finding difficulty). No maximum tolerated dose was identified. The recommended phase 2 dose was selected as 100 mg once daily. For ALK-positive patients, the proportion of patients who achieved an objective response was 19 (46%) of 41 patients (95% CI 31-63); for those who had received two or more TKIs, the proportion of patients with an objective response was 11 (42%) of 26 patients (23-63). In ROS1-positive patients, including seven crizotinib-pretreated patients, an objective response was achieved by six (50%) of 12 patients (95% CI 21-79). INTERPRETATION: In this phase 1, dose-escalation study, lorlatinib showed both systemic and intracranial activity in patients with advanced ALK-positive or ROS1-positive NSCLC, most of whom had CNS metastases and had previously had two or more TKI treatments fail. Therefore, lorlatinib might be an effective therapeutic strategy for patients with ALK-positive NSCLC who have become resistant to currently available TKIs, including second-generation ALK TKIs, and is being investigated in a phase 3 randomised controlled trial comparing lorlatinib to crizotinib (ClinicalTrials.gov, NCT03052608). FUNDING: Pfizer.

Lorlatinib Exposure-Response Analyses for Safety and Efficacy in a Phase I/II Trial to Support Benefit-Risk Assessment in Non-Small Cell Lung Cancer.

Lorlatinib is a small molecule inhibitor of anaplastic lymphoma kinase (ALK) and c-ROS oncogene 1 (ROS1) tyrosine kinases and is approved for the treatment of patients with ALK-positive advanced non-small cell lung cancer (NSCLC). In the phase I/II study (NCT01970865), potential exposure-response (E-R) relationships between lorlatinib and selected safety and efficacy end points were evaluated in patients with NSCLC. E-R relationships were assessed for safety end points with incidence > 10% in all treated patients (n = 328). In total, 4 safety end points were assessed: hypercholesterolemia grade ≥ 3, hypertriglyceridemia grade ≥ 3, weight gain grade ≥ 2, and treatment-emergent adverse events (TEAEs) grade ≥ 3. Using logistic regression, significant relationships were identified between lorlatinib plasma exposure and risk of hypercholesterolemia grade ≥ 3 (odds ratio (OR) 5.256) and risk of TEAE grade ≥ 3 (OR 3.214). The covariates baseline cholesterol and time on study prior to the event (TE) were associated with the probability of hypercholesterolemia grade ≥ 3. Baseline cholesterol and TE were found to have a statistically significant correlation with TEAE grade ≥ 3. Exposure-efficacy relationships were assessed for objective response rate (ORR; n = 197) and intracranial objective response rate (IC-ORR; n = 132). Lorlatinib plasma exposure was not identified as a statistically significant factor related to either efficacy end point. The only significant E-R relationships identified for efficacy were between baseline alkaline phosphatase and baseline amylase with IC-ORR (ORs 0.363 and 1.015, respectively). These findings support the lorlatinib indicated dose and dose modification guidelines regarding the management of lorlatinib-related AEs.

Correction to: The Effect of Rifampin on the Pharmacokinetics and Safety of Lorlatinib: Results of a Phase One, Open-Label, Crossover Study in Healthy Participants.

In the original article, the reference 4 has been published and cited incorrectly.

The Effect of Rifampin on the Pharmacokinetics and Safety of Lorlatinib: Results of a Phase One, Open-Label, Crossover Study in Healthy Participants.

INTRODUCTION: Lorlatinib is a third-generation tyrosine kinase inhibitor approved for the treatment of anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer; cytochrome P450 (CYP) 3A plays an important role in the metabolism of lorlatinib. METHODS: This phase 1, open-label, two-period, crossover study estimated the effect of oral rifampin (a strong CYP3A inducer) on the pharmacokinetics and safety of oral lorlatinib (NCT02804399). Healthy participants received single-dose lorlatinib 100 mg in period 1 followed by rifampin 600 mg/day (days 1-12) and single-dose lorlatinib 100 mg (day 8) in period 2. Blood samples were collected for 120 h after each dose of lorlatinib. RESULTS: When a single dose of lorlatinib was administered during daily dosing with rifampin (period 2), the area under the plasma concentration-time profile extrapolated to infinity (AUCinf) and maximum plasma concentration (Cmax) of lorlatinib were 14.74% [90% confidence interval (CI) 12.78%, 17.01%] and 23.88% (90% CI 21.58%, 26.43%), respectively, of those in period 1 (lorlatinib alone). A single dose of lorlatinib was well tolerated in period 1, but elevations in transaminase values were observed in all participants (grade 2-4 in 11 participants) within 1-3 days after a single dose of lorlatinib was administered with ongoing rifampin in period 2. Rifampin dosing was therefore halted. Transaminase levels subsequently returned to normal (median time to recovery: 15 days). No elevations in bilirubin were observed. CONCLUSIONS: The addition of a single dose of lorlatinib to daily dosing with rifampin significantly reduced lorlatinib plasma exposure relative to a single dose of lorlatinib administered alone and was associated with severe but self-limiting transaminase elevations in all healthy participants. These observations support the contraindication in the product label against concomitant use of lorlatinib with all strong CYP3A inducers. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT02804399.

Evaluating variability in tumor measurements from same-day repeat CT scans of patients with non-small cell lung cancer.

PURPOSE: To evaluate the variability of tumor unidimensional, bidimensional, and volumetric measurements on same-day repeat computed tomographic (CT) scans in patients with non-small cell lung cancer. MATERIALS AND METHODS: This HIPAA-compliant study was approved by the institutional review board, with informed patient consent. Thirty-two patients with non-small cell lung cancer, each of whom underwent two CT scans of the chest within 15 minutes by using the same imaging protocol, were included in this study. Three radiologists independently measured the two greatest diameters of each lesion on both scans and, during another session, measured the same tumors on the first scan. In a separate analysis, computer software was applied to assist in the calculation of the two greatest diameters and the volume of each lesion on both scans. Concordance correlation coefficients (CCCs) and Bland-Altman plots were used to assess the agreements between the measurements of the two repeat scans (reproducibility) and between the two repeat readings of the same scan (repeatability). RESULTS: The reproducibility and repeatability of the three radiologists' measurements were high (all CCCs, >or=0.96). The reproducibility of the computer-aided measurements was even higher (all CCCs, 1.00). The 95% limits of agreements for the computer-aided unidimensional, bidimensional, and volumetric measurements on two repeat scans were (-7.3%, 6.2%), (-17.6%, 19.8%), and (-12.1%, 13.4%), respectively. CONCLUSION: Chest CT scans are well reproducible. Changes in unidimensional lesion size of 8% or greater exceed the measurement variability of the computer method and can be considered significant when estimating the outcome of therapy in a patient.

Combined Pan-HER and ALK/ROS1/MET Inhibition with Dacomitinib and Crizotinib in Advanced Non-Small Cell Lung Cancer: Results of a Phase I Study.

INTRODUCTION: This phase I study investigated the activity of the irreversible pan-human epidermal growth factor receptor inhibitor dacomitinib in combination with the mesenchymal-epithelial transition factor/anaplastic lymphoma kinase/ROS proto-oncogene 1, receptor tyrosine kinase inhibitor crizotinib in advanced non-small cell lung cancer. METHODS: Patients with progression after at least one line of chemotherapy or targeted therapy received dacomitinib once daily and crizotinib once daily or twice daily, with doses escalated until intolerable toxicity; the expansion cohorts received the maximum tolerated dose of the combination. The primary objective was to define the recommended phase II dose; secondary objectives included assessment of safety and activity of the combination in epidermal growth factor receptor inhibitor-resistant patients and correlation with tumor biomarkers. RESULTS: Seventy patients were treated in the dose-escalation (n = 33) and expansion phases (n = 37), with the maximum tolerated dose defined as dacomitinib, 30 mg once daily, plus crizotinib, 200 mg twice daily. Grade 3 or 4 treatment-related adverse events were reported in 43% of patients: the most common were diarrhea (16%), rash (7%), and fatigue (6%). There were 16 deaths; none were considered treatment related. One patient (1%) had a partial response; 46% had stable disease. Most of the tumor samples analyzed had activating epidermal growth factor receptor gene (EGFR) mutations (18 of 20 [90%]); 50% (10 of 20) had a concurrent resistance mutation. Only one sample showed MMNG HOS Transforming gene (MET) amplification (the patient had progressive disease), whereas 59% (13 of 22) and 47% (14 of 30) had high levels of expression of epidermal growth factor receptor and mesenchymal-epithelial transition factor on the basis of H-scores, respectively. There was no apparent association between biomarker expression and antitumor activity. CONCLUSION: The combination of dacomitinib and crizotinib showed limited antitumor activity in patients with advanced non-small cell lung cancer and was associated with substantial toxicity.

Variability of lung tumor measurements on repeat computed tomography scans taken within 15 minutes.

PURPOSE: We use changes in tumor measurements to assess response and progression, both in routine care and as the primary objective of clinical trials. However, the variability of computed tomography (CT) -based tumor measurement has not been comprehensively evaluated. In this study, we assess the variability of lung tumor measurement using repeat CT scans performed within 15 minutes of each other and discuss the implications of this variability in a clinical context. PATIENTS AND METHODS: Patients with non-small-cell lung cancer and a target lung lesion ≥ 1 cm consented to undergo two CT scans within a period of minutes. Three experienced radiologists measured the diameter of the target lesion on the two scans in a side-by-side fashion, and differences were compared. RESULTS: Fifty-seven percent of changes exceeded 1 mm in magnitude, and 33% of changes exceeded 2 mm. Median increase and decrease in tumor measurements were +4.3% and -4.2%, respectively, and ranged from 23% shrinkage to 31% growth. Measurement changes were within ± 10% for 84% of measurements, whereas 3% met criteria for progression according to Response Evaluation Criteria in Solid Tumors (RECIST; ≥ 20% increase). Smaller lesions had greater variability of percent measurement change (P = .005). CONCLUSION: Apparent changes in tumor diameter exceeding 1 to 2 mm are common on immediate reimaging. Increases and decreases less than 10% can be a result of the inherent variability of reimaging. Caution should be exercised in interpreting the significance of small changes in lesion size in the care of individual patients and in the interpretation of clinical trial results.

A phase 2 study of weekly albumin-bound paclitaxel (Abraxane®) given as a two-hour infusion.

PURPOSE: Paclitaxel is an effective therapy for patients with solid tumors. While the albumin-bound formulation eliminates the hypersensitivity reaction caused by the Cremaphor solvent, significant peripheral neuropathy persists when given over the standard 30-min infusion time. We sought to determine if the incidence and severity of peripheral neuropathy could be reduced when the infusion time is lengthened to 2-h. METHODS: This was an open-label, single-arm, phase 2 study of albumin-bound paclitaxel given over 2 h. Twenty-five patients with advanced non-small-cell lung cancer were enrolled to determine whether the longer infusion reduced the severity of neuropathy compared to data from an earlier cohort of 40 similar patients treated over 30 min Patients received 125 mg/m(2) of albumin-bound paclitaxel IV over 2 h without premedication on days 1, 8, and 15 of a 28-day cycle. Radiologic assessment was performed every 8 weeks. RESULTS: There was a significant 0.45 grade decrease in average peripheral neuropathy experienced by patients in the 2-h group versus the 30-min group (90% CI, 0.03-0.87). There was, in addition, a significant decrease in grade ≥2 peripheral neuropathy in patients treated over 2 h versus 30 min (28% vs. 55%, 2-sided P = 0.04). A decrease in grade ≥2 neutropenia (20% vs. 48%, 2-sided P = 0.07) was also observed. The median survival, 11 months, was the same for both groups. CONCLUSION: Increasing the infusion time of albumin-bound paclitaxel from 30 min to 2 h resulted in a significant reduction in both average and grade ≥2 peripheral neuropathy without affecting survival.