Get 20M+ Full-Text Papers For Less Than $1.50/day. Start a 14-Day Trial for You or Your Team.

Learn More →

Clinical Management of Adverse Events Associated with Lorlatinib

Clinical Management of Adverse Events Associated with Lorlatinib Downloaded from https://academic.oup.com/oncolo/article/24/8/1103/6439309 by DeepDyve user on 01 February 2022 Lung Cancer Clinical Management of Adverse Events Associated with Lorlatinib a b c d e f g TODD M. BAUER, ENRIQUETA FELIP, BENJAMIN J. SOLOMON, HOLGER THURM, GERSON PELTZ, MARC D. CHIODA, ALICE T. SHAW a b Sarah Cannon Cancer Research Institute/Tennessee Oncology, PLLC, Nashville, Tennessee, USA; Vall d’Hebron University Hospital, c d Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain; Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia; Pfizer e f Oncology, La Jolla, California, USA; Pfizer Oncology, Groton, Connecticut, USA; Pfizer Oncology, New York, New York, USA; Massachusetts General Hospital, Boston, Massachusetts, USA Disclosures of potential conflicts of interest may be found at the end of this article. Key Words. Lorlatinib � Non-small cell lung cancer � Safety � Drug therapy management ABSTRACT Lorlatinib is a novel, highly potent, brain-penetrant, third- agent. Prescription of supportive therapy should also con- generation ALK/ROS1 tyrosine kinase inhibitor (TKI), which sider the potential for drug-drug interactions with lorlatinib has broad-spectrum potency against most known resistance via engagement of specific CYP450 enzymes. This article sum- mutations that can develop during treatment with crizotinib marizes the clinical experience from lorlatinib phase I investi- and second-generation ALK TKIs. The safety profile of lorlati- gators and was generated from discussion and review of the nib was established based on 295 patients who had received clinical study protocol and database to provide an expert the recommended dose of lorlatinib 100 mg once daily. consensus opinion on the management of the key adverse Adverse events associated with lorlatinib are primarily mild reactions reported with lorlatinib, including hyperlipidemia, to moderate in severity, with hypercholesterolemia (82.4%), central nervous system effects, weight increase, edema, periph- hypertriglyceridemia (60.7%), edema (51.2%), peripheral eral neuropathy, and gastrointestinal effects. Overall, lorlatinib neuropathy (43.7%), and central nervous system effects 100 mg once daily has a unique safety profile to be consid- (39.7%) among the most frequently reported. These can be ered when prescribed, based on the recent U.S. Food and effectively managed with dose modification and/or standard Drug Administration approval, for the treatment of patients supportive medical therapy, as indicated by a low incidence with ALK-positive metastatic non-small cell lung cancer previ- of permanent discontinuations due to adverse reactions. ously treated with a second-generation ALK TKI. The Oncologist Most patients (81.0%) received at least one lipid-lowering 2019;24:1103–1110 Implications for Practice: Despite the advancement of second-generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs), the emergence of resistance and progression of central nervous system metastases remain clinically significant problems in ALK-positive non-small cell lung cancer. Lorlatinib is a potent, brain-penetrant, third-generation, macrocyclic ALK/ROS1 TKI, with broad-spectrum potency against most known resistance mutations that can develop during treatment with existing first- and second-generation ALK TKIs. This article provides recommendations for the clinical man- agement of key adverse reactions reported with lorlatinib. BACKGROUND Rearrangements of the anaplastic lymphoma kinase (ALK) of acquired (or secondary) resistance that occurs through gene are found in 3%–5% of patients with non-small cell lung several molecular mechanisms, including development of sec- cancer (NSCLC) [1–4] and represent a clinically and molecu- ondary mutations within the ALK kinase domain and activation larly distinct subtype of NSCLC. Standard therapy for patients of alternative signaling pathways [9]. More potent second- with ALK-positive NSCLC includes crizotinib, a multitargeted generation ALK TKIs were developed to surmount the develop- ALK/ROS1/MET tyrosine kinase inhibitor (TKI) [5] and, more ment of crizotinib resistance in ALK-positive NSCLC and have recently, second-generation ALK TKIs [6–8]. However, most demonstrated improved response rates in crizotinib-refractory patients treated with crizotinib relapse over time because and treatment-naïve patients [7, 8, 10, 11]. However, most Correspondence: Todd M. Bauer, M.D., Sarah Cannon Cancer Research Institute/Tennessee Oncology, PLLC, 250 25th Ave. N, Nashville, Tennessee 37203, USA. Telephone: 1-615-329-7274; e-mail: tbauer@tnonc.com Received June 27, 2018; accepted for publication February 15, 2019; published Online First on March 19, 2019. http://dx.doi.org/10.1634/theoncologist.2018-0380 The Oncologist 2019;24:1103–1110 www.TheOncologist.com © AlphaMed Press 2019 Downloaded from https://academic.oup.com/oncolo/article/24/8/1103/6439309 by DeepDyve user on 01 February 2022 1104 Management of Adverse Events with Lorlatinib patients will eventually develop resistance to second-generation based on prior treatment and rearrangement status (expansion ALK TKIs [12]. cohorts 1–5, ALK-positive; expansion cohort 6, ROS1-positive), details of which have been previously presented [21]. In April Treatment options following the emergence of resistance to a second-generation ALK TKI are limited, with platinum- 2017, lorlatinib was granted breakthrough therapy designation by the U.S. Food and Drug Administration (FDA) in patients based chemotherapy as the current standard of care. How- ever, the associated toxicities, consisting of adverse events with ALK-positive advanced NSCLC previously treated with one or more ALK inhibitors and, in November 2018, the FDA such as nausea, vomiting, and neutropenia, can negatively impact patients’ quality of life. Although there are no pub- granted lorlatinib an accelerated approval for the treatment of patients with ALK-positive metastatic NSCLC who had dis- lished data on the antitumor activity of chemotherapy after second-generation ALK TKIs, response rates of 27%–45% have ease progression on crizotinib and at least one other ALK TKIorwho haddisease progressiononalectinib or ceritinib as been reported with platinum- and pemetrexed-based chemo- therapy in the first-line treatment of ALK-positive advanced the first ALK TKI. The phase III CROWN study (NCT03052608) comparing lorlatinib with crizotinib as first-line treatment NSCLC [5, 8], and response rates ranging from 7% to 11% have been reported with single-agent chemotherapy in among patients with ALK-positive advanced NSCLC is currently enrolling patients. patients previously treated with a platinum doublet and crizotinib [13–15]. Lorlatinib is a novel, highly potent, third-generation, macro- cyclic ALK/ROS1 TKI that competitively binds to the adenosine LORLATINIB:SAFETY AND TOLERABILITY triphosphate-binding pocket, blocking ALK-dependent onco- genic signaling. Lorlatinib was also designed to penetrate the Overview The safety profile of lorlatinib was established based on blood–brain barrier in part by minimizing p-glycoprotein- 1-mediated efflux, which can lead to poor blood–brain barrier 295 patients who had received the recommended dose of lorlatinib 100 mg once daily (QD) in the fully recruited, penetration [16, 17]. Lorlatinib has broad-spectrum potency against most known resistance mutations that can develop ongoing phase I/II study (NCT01970865). This pooled group comprised 17 patients from the phase I portion of the during treatment with crizotinib and second-generation ALK TKIs, including the difficult-to-treat ALK G1202R mutation [18]. study, 275 patients from the phase II portion, and 3 patients from a Japanese lead-in cohort—an evaluation study of the safety and tolerability of lorlatinib in Japanese patients LORLATINIB:PHARMACOLOGY conducted before sites in Japan could participate in the In preclinical studies, advantageous pharmacokinetic proper- phase II study because of lack of documented experience ties have been reported for lorlatinib including low plasma in this patient population. The data presented in this article clearance, 100% oral bioavailability, and a moderate volume are based on a cutoff date of March 15, 2017. of distribution [16]. Lorlatinib may be taken with or without The incidence and management of the most frequent food and is rapidly absorbed (peak plasma concentrations adverse reactions (i.e., adverse drug reactions) with lorlatinib, occurring 1–2 hours after dosing), with a terminal elimination particularly those occurring in ≥10% of patients, are reported. half-life of 19.0–28.8 hours (Pfizer, data on file). The high Adverse drug reactions are defined as those adverse events blood–brain barrier penetration of lorlatinib is supported by a that, after internal clinical and safety review applying medical mean ratio of cerebrospinal fluid/plasma (unbound) of 0.75 judgment, were determined to be likely associated with the [19]. Lorlatinib is metabolized primarily by cytochrome P450 study treatment. This is in contrast to the broad category of (CYP)3A, CYP2C19, and CYP2C8 and uridine 5’-diphospho- all-causality adverse events, which may or may not have an glucuronosyltransferase and has also exhibited time-dependent established causal relationship. It is further important to note inhibition of CYP3A4/5 as well as induction of CYP2B6 and that the definitions and reporting thresholds for adverse reac- CYP3A4 (Pfizer, data on file). Thus, lorlatinib may have the tions can vary across different regulatory health authorities, potential to alter the pharmacokinetics of other coadministered and in certain circumstances, these concepts can be used drugs that are metabolized by CYP2B6 or CYP3A. A phase I, interchangeably. In the phase I/II study (based on the data open-label, crossover study (ClinicalTrials.gov identifier: cutoff of March 15, 2017), adverse reactions consisted of NCT02804399) found that concomitant administration of lor- adverse events including hypercholesterolemia, hypertri- latiniband rifampin ledtoelevatedaspartate andalanine ami- glyceridemia, central nervous system (CNS) effects (mood notransferase levels (Pfizer, data on file). Therefore, the use of disorder, cognitive disorder, and speech disorder), weight strong CYP3A4/5 inducers with lorlatinib is contraindicated. increase, edema, peripheral neuropathy, diarrhea, constipa- tion, fatigue, arthralgia, and vision disorder. Additional adverse events of clinical interest included lipase increase and atrio- LORLATINIB:CLINICAL EXPERIENCE ventricular (AV) block. In an ongoing phase I/II study (NCT01970865), lorlatinib dem- Adverse reactions in this pooled safety analysis population onstrated clinically meaningful benefit, including substantial of 295 patients treated with lorlatinib 100 mg QD are shown intracranial efficacy, among patients with ALK-positive or in Table 1. Hyperlipidemia, edema, and peripheral neuropathy ROS1-positive advanced NSCLC who were treatment naïve were among the most frequently reported adverse reactions or who had received a range of prior ALK inhibitors with or with lorlatinib treatment. Most adverse reactions were grade without chemotherapies [19, 20]. Patients in the phase II 1 or 2 in severity, with few grade ≥ 3 adverse reactions reported portion of this study were enrolled into six expansion cohorts (Table 1). Serious adverse reactions occurred in 9 patients © AlphaMed Press 2019 Downloaded from https://academic.oup.com/oncolo/article/24/8/1103/6439309 by DeepDyve user on 01 February 2022 Bauer, Felip, Solomon et al. 1105 Table 1. Adverse reactions in ≥10% of all patients or Grade dose delay (3.4% and 4.7%, respectively) or dose reduction ≥3 adverse reactions in any patient treated with lorlatinib (0.7% and 1.7%, respectively) and did not result in any per- 100 mg once daily manent discontinuations across the study. In most cases, these typically asymptomatic adverse events were easily man- Pooled lorlatinib 100 mg aged with appropriate medical therapy (i.e., lipid-lowering once daily (N = 295) Adverse drug agents) and dose interruptions, coupled with dose modifica- reactions, n (%) All grades Grade 3 Grade 4 tions for more severe (grade ≥3) and difficult-to-treat adverse Hypercholesterolemia 243 (82.4) 41 (13.9) 5 (1.7) events (Table 2). Hypertriglyceridemia 179 (60.7) 39 (13.2) 7 (2.4) Most patients (81.0%) received at least one lipid-lowering Edema 151 (51.2) 7 (2.4) 0 (0.0) agent and commenced treatment within 3 weeks of the first lor- Peripheral neuropathy 129 (43.7) 7 (2.4) 0 (0.0) latinib dose (median time to start of lipid-lowering medication, 20 days [range, 1–190]). Among 226 patients who received a Cognitive effects 68 (23.1) 5 (1.7) 0 (0.0) lipid-lowering agent for hypercholesterolemia and 198 who Fatigue 68 (23.1) 1 (0.3) 0 (0.0) received a lipid-lowering agent for hypertriglyceridemia, 22.1% Mood effects 62 (21.0) 4 (1.4) 0 (0.0) and 30.8% of patients required the addition of another lipid- Weight increase 61 (20.7) 7 (2.4) 0 (0.0) lowering agent, respectively. The most commonly prescribed Arthralgia 58 (19.7) 0 (0.0) 0 (0.0) lipid-lowering agent was rosuvastatin (n =124; 42.0% of Diarrhea 52 (17.6) 2 (0.7) 0 (0.0) patients). Treatment with a statin is recommended at the first sign of elevated cholesterol (upper limit of normal, Constipation 42 (14.2) 0 (0.0) 0 (0.0) 300 mg/dL [upper limit of normal, 7.75 mmol/L]) and/or tri- Vision disorder 39 (13.2) 1 (0.3) 0 (0.0) glyceride levels (150–300 mg/dL [1.71–3.42 mmol/L]). The Speech effects 28 (9.5) 1 (0.3) 0 (0.0) choice and dosing of statins may be guided by information Clustered term comprising adverse events that represent similar on the differential metabolism by the CYP450 pathway (sup- clinical symptoms/syndromes. plemental online Table 1). Pitavastatin, pravastatin, or rosu- Based on Common Terminology Criteria for Adverse Events (v4.03). vastatin should initially be considered based on their low involvement with specific CYP450 enzymes that can interact (3.0%), and the most frequently reported were cognitive disor- with lorlatinib (e.g., CYP3A4) [22]. The addition of fibrates or der (1.0%) and edema (0.7%). fish oils is considered effective in lowering triglyceride levels Temporary dose interruptions and dose reductions asso- if treatment beyond statins is required [23]. Of these, fenofi- ciated with adverse reactions were reported in 21.7% and brate can be administered first as it has the least involvement 19.7% of patients, respectively. The most common cause for with the associated CYP450 enzymes, followed by fish oils dose interruptions and dose modifications was edema (5.8% and nicotinic acid [24–26]. Of note, the concomitant use of and 6.1% of patients, respectively). Overall, the incidence gemfibrozil and some statins is not recommended. In partic- of permanent discontinuations due to adverse reactions ular, coadministration of gemfibrozil with simvastatin is con- was low (n = 6 [2.0%]). The adverse reactions that led to traindicated [27]. Ezetimibe may also be considered if treatment permanent treatment discontinuations were cognitive dis- with statins and fenofibrate is ineffective. order (n = 2), mood disorder (n = 2), edema (n =1), and Dose interruptions are recommended if cholesterol fatigue (n =1). levels reach >500 mg/dL and/or triglyceride levels reach This article summarizes the clinical experience from lorla- >1,000 mg/dL despite the use of lipid-lowering therapies. tinib phase I investigators and was generated from discus- Lorlatinib should be withheld, while maximizing lipid-lowering sion and review of the clinical study protocol and database treatment, until severity is reduced before rechallenging at to provide an expert consensus opinion on the management the same dose. Reducing the lorlatinib dose is suggested only of the key adverse reactions reported with lorlatinib, includ- if cholesterol levels >500 mg/dL and/or triglyceride levels ing hyperlipidemia, CNS effects, weight increase, edema, >1,000 mg/dL recur (Table 2). peripheral neuropathy and gastrointestinal effects. Lipase In light of the frequent occurrence of hyperlipidemia, increase and AV block adverse events are also discussed. patients should be informed of the likelihood of requiring lipid-lowering therapy or that an increase in dose may be neces- Management of Specific Adverse Events sary for those patients already receiving lipid-lowering agents. Hyperlipidemia In addition, patients should be aware that monitoring of serum Hyperlipidemia, comprising the cluster terms hypercholesterol- cholesterol and triglyceride levels is to be expected before and emia and hypertriglyceridemia, was the most common adverse throughout the course of treatment with lorlatinib (supplemen- reaction reported with lorlatinib and usually occurred within tal online Table 2). However, patients should be advised that the first few weeks of treatment (median time to onset, hyperlipidemia associated with lorlatinib treatment is easily 15 days [range, 1–219]; supplemental online Fig. 1). Hypercho- managed and resolvable through lipid-lowering therapy and/or lesterolemia and hypertriglyceridemia were reported in 82.4% dose modifications. and 60.7% of patients in the pooled safety group, respectively, and both events were mostly grade 1 or 2 in severity. Grade 3/4 CNS Effects hypercholesterolemia and hypertriglyceridemia both occurred A broad spectrum of CNS effects can occur in patients at a frequency of 15.6%. However, hypercholesterolemia receiving lorlatinib, and the following section summarizes and hypertriglyceridemia were not common reasons for the changes in cognitive function, mood, and speech that www.TheOncologist.com © AlphaMed Press 2019 Downloaded from https://academic.oup.com/oncolo/article/24/8/1103/6439309 by DeepDyve user on 01 February 2022 1106 Management of Adverse Events with Lorlatinib Table 2. Dose modification guidelines for lorlatinib-related hyperlipidemias by severity Severity Guidance Mild: � Introduce or modify lipid-lowering therapy Cholesterol ULN–300 mg/dL � Continue at the same lorlatinib dose OR Triglycerides 150–300 mg/dL Moderate: Cholesterol >300–400 mg/dL OR Triglycerides >300–500 mg/dL Severe: � Introduce lipid-lowering agent or increase dosage of ongoing lipid-lowering Cholesterol >400–500 mg/dL therapy, or change to a new lipid-lowering therapy OR � Continue at the same lorlatinib dose without interruption Triglycerides >500–1,000 mg/dL Life threatening: � Introduce lipid-lowering agent or increase dosage of ongoing lipid-lowering Cholesterol >500 mg/dL therapy, or change to a new lipid-lowering therapy OR � Withhold lorlatinib dose until hyperlipidemia is moderate or mild before Triglycerides >1000 mg/dL rechallenging at same dose while maximizing lipid-lowering therapy � If severe hyperlipidemia recurs despite maximal lipid-lowering therapy, reduce lorlatinib dose by one dose level (by 25 mg) Abbreviation: ULN, upper limit of normal. Table 3. Dose modification guidelines for lorlatinib-related 2 or 3 CNS adverse events, lorlatinib should be withheld until central nervous system effects by CTCAE grade recovery to grade ≤1 before rechallenging at a reduced dose. Permanent discontinuation from lorlatinib is recommended CTCAE grade Guidance for grade 4 CNS effects. In addition, patients and their caregivers Grade 1: Mild � Continue at the same should be instructed to report any changes in cognitive function, dose or withhold dose mood, or speech to their health care provider. until recovery to baseline � Rechallenge at the same dose or reduce dose by Mood Effects. Behavioral alterations and mood changes asso- one dose level (by 25 mg) ciated with lorlatinib in clinical studies were collected under Grade 2: Moderate � Withhold dose until OR adverse event is grade ≤1 the cluster term “mood effects” and are showninTable 4. Grade 3: Severe � Rechallenge at one These effects occurred at a frequency of 21.0%, with a median reduced dose level time to onset of 43 days (range, 1–452 days). Irritability, anxi- (by 25 mg) Grade 4: Life-threatening/ � Permanently discontinue ety, depression, and affect lability were the most common urgent intervention indicated lorlatinib mood adverse events reported. Mood changes observed with Based on CTCAE (v4.03). lorlatinib were mostly mild in severity (19.7%), with no grade Abbreviation: CTCAE, Common Terminology Criteria for Adverse Events. 4 adverse events reported. The overall frequency of mood effects was comparable between patients <65 years of age have been reported in patients receiving lorlatinib. These (21.6%) and those ≥65 years (18.5%); however, they were adverse reactions were reported at a frequency of 39.7%, reported more frequently in non-Asian (27.3%) compared with with 11.9% of patients experiencing more than one type of Asian patients (10.2%). Most patients with mood effects will CNS effect (supplemental online Fig. 2). Baseline CNS metas- describe feeling more irritable, more prone to impatience or tases were present in 84 (71.8%) of 117 patients with CNS anger, or sometimes more anxious. When patients first start effects (supplemental online Fig. 3). Of the 84 patients with treatment, some report feeling a little “energized” or even CNS effects and baseline CNS metastases, 22 (26.2%) had “buzzed.” Patients have also reported “feeling flat” and/or received prior whole-brain radiation therapy (supplemental “feeling less excited about things.” Additional assessments of online Fig. 4). CNS adverse reactions were generally mild in mood and suicidal ideation and behavior were a requirement severity and intermittent and improved or resolved upon of the phase II study and were administered to patients at the dose modifications. Out of 117 patients who experienced beginning of each cycle up to cycle 6 and then every other CNS effects, 24 required ≥1dose modification (temporary cycle thereafter. Based on the phase II portion (n = 275), there discontinuation and/or dose reduction), with 15 (62.5%) of were no trends in the Beck Depression Inventory-II summary these patients experiencing resolution of their CNS effects. data to suggest worsening of symptoms during treatment with The median time to resolution of CNS effects was 12.5 days lorlatinib. Likewise, there were no trends in the Columbia- (range 2–112). Recurrence of CNS effects upon rechallenge Suicide Severity Rating Scale group summary data to suggest a at the same and reduced dose occurred in six (25.0%) and notable shift in suicidal ideation or behavior during treatment seven (29.2%) patients, respectively. General dose modifica- with lorlatinib (Pfizer, data on file). Mood effects related to lor- tion guidelines appropriate for any of the CNS effects are latinib were associated with dose interruptions and reductions outlined in Table 3. Dose interruptions should be considered in eight (2.7%) and seven (2.4%) patients, respectively. Out of in the presence of grade 1 CNS effects and enforced until the 12 mood events that required dose modification (i.e., dose recovery to baseline before restarting lorlatinib at the same reduction, temporary discontinuation, or both), 8 (66.7%) dose or, if required, at a lower dose. For patients with grade events resolved. The median time to resolution was 14 days © AlphaMed Press 2019 Downloaded from https://academic.oup.com/oncolo/article/24/8/1103/6439309 by DeepDyve user on 01 February 2022 Bauer, Felip, Solomon et al. 1107 Table 4. Mood disorder adverse events with lorlatinib Table 5. Cognitive disorder adverse events with lorlatinib Pooled lorlatinib 100 mg Pooled lorlatinib 100 mg once daily (N = 295) once daily (N = 295) Preferred term, n (%) All grades Grade 3 Grade 4 Preferred term, n (%) All grades Grade 3 Grade 4 Any adverse event 62 (21.0) 4 (1.4) 0 (0.0) Any adverse event 68 (23.1) 5 (1.7) 0 (0.0) Irritability 18 (6.1) 2 (0.7) 0 (0.0) Memory impairment 26 (8.8) 0 (0.0) 0 (0.0) Anxiety 15 (5.1) 1 (0.3) 0 (0.0) Cognitive disorder 18 (6.1) 2 (0.7) 0 (0.0) Depression 12 (4.1) 1 (0.3) 0 (0.0) Amnesia 16 (5.4) 0 (0.0) 0 (0.0) Affect lability 7 (2.4) 0 (0.0) 0 (0.0) Confusional state 11 (3.7) 2 (0.7) 0 (0.0) Personality change 5 (1.7) 0 (0.0) 0 (0.0) Disturbance in attention 7 (2.4) 0 (0.0) 0 (0.0) Mood swings 3 (1.0) 0 (0.0) 0 (0.0) Delirium 2 (0.7) 1 (0.3) 0 (0.0) Affective disorder 2 (0.7) 0 (0.0) 0 (0.0) Mental impairment 2 (0.7) 0 (0.0) 0 (0.0) Aggression 2 (0.7) 0 (0.0) 0 (0.0) Attention deficit/hyperactivity 1 (0.3) 0 (0.0) 0 (0.0) disorder Agitation 2 (0.7) 1 (0.3) 0 (0.0) Dementia 1 (0.3) 0 (0.0) 0 (0.0) Mood altered 2 (0.7) 0 (0.0) 0 (0.0) Reading disorder 1 (0.3) 0 (0.0) 0 (0.0) Depressed mood 1 (0.3) 0 (0.0) 0 (0.0) Based on Common Terminology Criteria for Adverse Events (v4.03). Euphoric mood 1 (0.3) 0 (0.0) 0 (0.0) Mania 1 (0.3) 0 (0.0) 0 (0.0) analysis, there was little evidence of any systematic decline in Based on Common Terminology Criteria for Adverse Events (v4.03). cognition associated with lorlatinib (Pfizer, data on file). Cognitive effects were among the most frequently reported adverse events (range 2–112). Recurrence upon rechallenge at a reduced associated with dose interruptions (3.7%) and dose reductions dose was reported with four (33.3%) mood events; no recur- (2.7%). Out of the 33 cognitive effects that required dose rence following rechallenge at the same dose was reported. modification(s), 22 (66.7%) resolved. The median time to reso- Affect lability and anxiety resulted in permanent treatment lution was 10 days (range, 3–39). Seven (21.2%) cognitive discontinuation in one patient each. effects recurred upon rechallenge with the same dose of lor- Effects on mood should be discussed with patients latinib and four (12.1%) recurred with a reduced dose. Two before lorlatinib is administered. It is particularly important patients permanently discontinued lorlatinib as a result of cog- to review these effects with patients who have pre-existing nitive disorder (n = 1) and confusional state (n =1). psychiatric conditions. Caregivers and family members, as The possibility of cognitive-related adverse reactions should well as patients, should also be encouraged to report any be discussed with patients and caregivers before starting lorlati- changes in patients’ mood during treatment with lorlatinib nib treatment, along with advice on how to minimize the in the event that patients are unaware of such changes. impact on daily activities (e.g., setting reminders). Patients These adverse events are temporary and reversible upon should be advised to inform their health care provider if they dose interruption or reduction. experience any changes in cognitive functioning. As with all CNS effects, dose modifications, imposed at low thresholds, are generally effective in reversing these adverse events (Table 3), Cognitive Effects. Cognitive effects (cluster term) were re- and the importance of dose reduction should be emphasized if ported in 23.1% of patients treated with lorlatinib in the patients’ usual activities or relationships are impaired by cogni- pooled safety analysis. These adverse events, which most tive or mood effects. commonly included memory impairment, cognitive disorder, and amnesia, usually presented within the first 2 months of treatment (median time to onset, 53 days [range, 1–423]) Speech Effects. Speech effects (cluster term) occurred in and were mainly grade ≤ 2 in severity (21.4%; Table 5). The 9.5% of patients, with a median time to onset of 42 days frequency of cognitive effects was comparable between age (range, 1–404). Dysarthria, slow speech, and speech disorder groups (<65 years [22.4%] or ≥ 65 years [25.9%]); however, were reported in 3.7%, 3.4%, and 2.4% of patients, respec- they were reported at a higher frequency in non-Asian (28.0%) tively (supplemental online Table 3). Overall, these adverse compared with Asian patients (12.0%). Five grade 3 cognitive events were predominantly mild in severity (grade 1, 8.5%). effects were reported: cognitive disorder (n = 2), confusional One patient required a dose reduction and interruption as a state (n = 2), and delirium (n = 1). Patients have reported result of dysarthria. Of the three speech events that required experiences described as “sluggish thought,”“fogginess,” dose modification(s), two (66.7%) events resolved. The median “trouble connecting the dots,” difficulty multitasking, difficulty time to resolution was 38.5 days (range, 35–42). One (33.3%) finding the right words, issues with short-term memory or out of three speech events with dose modifications recurred recall, and confusion and hallucinations in severe cases. An upon rechallenge at the same dose of lorlatinib; no recurrence assessment of cognitive function, which tested verbal learning, was reported with rechallenge at a reduced dose. No patients psychomotor function, delayed recall, attention, and working permanently discontinued treatment because of speech effects. memory, was conducted in the phase II portion and validated Speech effects have been reported by patients as a percep- by a central vendor (Cogstate, Inc., New Haven, CT). From this tion of slowed speech or difficulty in word finding. Although www.TheOncologist.com © AlphaMed Press 2019 Downloaded from https://academic.oup.com/oncolo/article/24/8/1103/6439309 by DeepDyve user on 01 February 2022 1108 Management of Adverse Events with Lorlatinib the altered speech experienced is typically mild, the ability to Table 6. General dose modification guidelines for lorlatinib- tolerate such adverse events can vary between patients. related adverse reactions by CTCAE grade Therefore, patients should be counseled on the potential CTCAE grade Guidance for speech effects at the time of treatment initiation and Grade 1: Mild � Continue at the same dose or should be reassured that these adverse events are revers- OR reduce by one dose level ible following dose modifications or treatment cessation, if Grade 2: Moderate (by 25 mg) required. Patients should also notify their health care pro- Grade 3: Severe � Withhold dose until adverse vider if they experience any changes in their speech. OR event is grade ≤2 or returned Grade 4: Life-threatening/ to baseline (if not considered a urgent intervention safety risk for the patient) Weight Increase indicated � Rechallenge at one reduced Reports of weight increases among patients treated with lorlati- dose level (by 25 mg) nib usually presented within 2 months of treatment initiation Based on CTCAE (v4.03). (median time to onset, 64 days [range, 1–519]). Of 282 evalu- Permanent discontinuation is recommended if patient is unable to tolerate lorlatinib 50 mg taken orally once daily. able patients in the pooled safety group, 87 (30.9%) had a Abbreviation: CTCAE, Common Terminology Criteria for Adverse Events. 10%–20% increase of their baseline body weight and 38 (13.5%) had a >20% increase of their baseline body weight. The median of maximum percent change from base- management of edema. The addition of spironolactone can line was 11.4% (range, 0.2–55.2). However, weight increase also be beneficial in the treatment of edema refractory to furo- was only reported as an adverse event in 61 patients (20.7%), semide monotherapy. However, if edema persists or worsens, most of which were grade ≤2 in severity (18.3%). An increase general dose modification guidance can be used with lorlatinib in weight was reported as an adverse event in 4.1% of treatment and held until improvement to grade ≤2 (if not a patients at Cycle 1, 13.3% of patients by Cycle 4, and 23.4% of safety risk) or returned to baseline and rechallenged at a patients by Cycle 8. An increase in appetite has been reported reduced dose (Table 6). by some patients, suggesting that body weight increase may potentially be associated with increased caloric intake and a heightened desire to eat; however, causality has not been Peripheral Neuropathy determined. Additionally, cases of weight gain (≥10% increase Peripheral neuropathy (cluster term) associated with lorlati- from baseline) reported concurrently with edema were lim- nib was reported at a frequency of 43.7%, with a median ited and are shown in supplemental online Figure 5. time to onset of 77 days (range, 1–723). Within the cluster Two patients required dose interruptions and two required term, the most common adverse events reported were par- dose reductions as a result of weight increase associated esthesia (13.2%) and neuropathy peripheral (11.2%). Other with lorlatinib treatment. Although relatively uncommon, dose peripheral neuropathy adverse events seen with lorlatinib modifications (Table 6) should be applied in more severe cases included peripheral sensory neuropathy and muscular weak- of weight gain. ness (Table 7). In general, peripheral neuropathy adverse Food intake counseling, dietary advice from a nutrition- events were mild in severity (grade ≤2, 41.4%) and revers- ist, and the addition of exercise also appear to be effective ible following dose modifications or standard medical ther- weight management strategies, although nonadherence can apy. Symptoms were often described as tingling, numbness, be an issue. Patients should be advised from the outset that and pain at night in extremities (especially in patients experienc- they are likely to experience some degree of weight gain. ing symptoms similar to carpal tunnel syndrome). In patients This will ensure that patients are prepared and can expect with pre-existing carpal tunnel syndrome, symptoms often wors- to implement some lifestyle adjustments. ened when they received lorlatinib. Patients with peripheral neuropathy often also reported adverse events of weight gain Edema and/or edema (71.3%); overlap of these three adverse events is Treatment with lorlatinib was associated with edema (51.2%), shown in supplemental online Figure 6. with peripheral edema arising as the most frequently reported Peripheral neuropathy was among the most frequently event (41.7%). Other adverse events reported within the edema reported adverse events associated with dose interruptions cluster term were edema (7.5%), peripheral swelling (6.1%), (4.1%) and dose reductions (4.1%) but responded well to these generalized edema (0.7%), and swelling (0.7%). The median dose modifications. General guidance on dose modifications time to onset of edema was 42 days (range, 1–232), with a should be considered in higher-severity cases (Table 6). Thus, if median duration of 163 days. Most adverse events were mild grade ≥3 peripheral neuropathy occurs following administration in severity (grade ≤2, 48.8%), and only 2.4% of patients expe- of lorlatinib, treatment should be temporarily discontinued rienced grade 3 events. Edema was the most common cause until adverse events are reduced to grade ≤2(if nota safety of dose interruptions (5.8%) and dose reductions (6.1%) in the risk) or returned to baseline and the patient rechallenged at a pooled safety analysis group. reduced lorlatinib dose. Treatment with vitamin B and vitamin In practice, compression stockings, leg elevations, and life- B and medications for pain associated with peripheral style modifications, such as increased exercise and limiting neuropathy (e.g., gabapentin or pregabalin) may also pro- dietary salt, should initially be considered in patients with low- vide symptom relief in some cases. For carpal tunnel syn- grade edema before commencing with dose modifications. drome, the use of a night splint has been found to provide These conservative measures, in combination with diuretics improvement in some patients. However, in more signifi- (usually furosemide), have shown to be effective in the cant cases, patients may opt for release surgery. © AlphaMed Press 2019 Downloaded from https://academic.oup.com/oncolo/article/24/8/1103/6439309 by DeepDyve user on 01 February 2022 Bauer, Felip, Solomon et al. 1109 Table 7. Peripheral neuropathy adverse events with AV Block and Other Electrocardiogram Findings lorlatinib In a study of healthy volunteers who were administered lorla- tinib, analysis of electrocardiogram (ECG) data revealed some Pooled lorlatinib 100 mg evidence of PR prolongation, although no adverse events once daily (N = 295) associated with AV block were reported. However, of 295 Preferred term, N (%) All grades Grade 3 Grade 4 patients treated with lorlatinib, asymptomatic first-degree AV Any adverse event 129 (43.7) 7 (2.4) 0 (0.0) block (grade 1 in severity) was reported in 2 patients (0.7%). Paresthesia 39 (13.2) 1 (0.3) 0 (0.0) Complete AV block was reported for one patient (0.3%; grade 3) Neuropathy peripheral 33 (11.2) 2 (0.7) 0 (0.0) and led to temporary discontinuation from treatment, although Peripheral sensory neuropathy 25 (8.5) 1 (0.3) 0 (0.0) it should be noted that this patient had pre-existing second- degree AV block. There were no other dose modifications or dis- Muscular weakness 15 (5.1) 1 (0.3) 0 (0.0) continuations as a result of AV block. Gait disturbance 9 (3.1) 1 (0.3) 0 (0.0) ECG QT prolongation was reported in 19 patients (6.4%), Carpal tunnel syndrome 8 (2.7) 1 (0.3) 0 (0.0) most of which were grade ≤2, although one event was grade Hypoesthesia 8 (2.7) 0 (0.0) 0 (0.0) 3 in severity and required temporary discontinuation. None of Dysesthesia 5 (1.7) 0 (0.0) 0 (0.0) these events resulted in permanent treatment discontinuation. Before initiating treatment with lorlatinib, patients should be Neuralgia 3 (1.0) 1 (0.3) 0 (0.0) informed of the potential risks of AV block and advised to con- Neurotoxicity 3 (1.0) 0 (0.0) 0 (0.0) tact their health care provider immediately if they experience Burning sensation 1 (0.3) 0 (0.0) 0 (0.0) any new chest pain or discomfort, changes in heartbeat, palpi- Formication 1 (0.3) 0 (0.0) 0 (0.0) tations, dizziness, lightheadedness, or fainting, and changes in Sensory disturbance 1 (0.3) 0 (0.0) 0 (0.0) or new use of heart or blood pressure medication. For patients Based on Common Terminology Criteria for Adverse Events (v4.03). with pre-existing PR prolongation, ECG monitoring should be conducted throughout the course of treatment (supplemental In addition, peripheral neuropathy may be associated online Table 2). For patients who develop AV block, dose modi- with peripheral edema (primarily of the upper extremities). fication may be required depending upon the degree of AV In such instances, treatment with diuretics might improve block and whether the patient exhibits symptoms. Dose modi- peripheral neuropathy symptoms as well as reduce edema. fication guidelines for patients with AV block are described in supplemental online Table 4. Increase in Lipase SUMMARY In thepooledsafetyanalysisgroup,anincreaseinlipasewas Lorlatinib has an unique safety profile, distinct from those of reported as an adverse event in 10.8% of patients treated with other ALK TKIs, and is generally well tolerated with a low inci- lorlatinib. Of 290 evaluable patients, lipase increases were dence of permanent discontinuations due to adverse reac- reported as a laboratory abnormality (any grade) in 77 patients tions (n = 6 [2.0%]). Temporary dose interruptions and dose (26.6%), most of which were grade ≤2 (17.6%). Pancreatitis reductions associated with adverse reactions were reported was rare and reported in 1 of 295 patients; however, other in 21.7% and 19.7% of patients, respectively. potential confounding factors were noted with this patient. Hyperlipidemia is the most common adverse drug reaction Lipase elevations were often sporadic throughout the course of associated with lorlatinib and is largely manageable with lipid- treatment and episodic in some patients. Based on laboratory lowering therapy. In our analysis, most patients (81.0%) received data, increases in lipase generally occurred within 2 months of at least one lipid-lowering agent, and 22.1% and 30.8% required starting lorlatinib treatment (median time to onset, 62 days two or more agents for hypercholesterolemia and hypertrigly- [range, 7–619]). Distributions of lipase levels across treatment ceridemia, respectively. Therefore, patients should be informed cycles are shown in supplemental online Figure 7. that they may experience these adverse events and be moni- Dose interruptions and dose reductions due to lipase ele- tored throughout treatment. The CNS effects associated with vations were reported in nine (3.1%) and three (1.0%) patients, lorlatinib generally improved or resolved following dose modifi- respectively. General guidance on dose modifications should cations. Patients, and importantly patients’ family members be applied to grade ≥3 adverse events (Table 6). and/or caregivers, should be advised to alert health care pro- viders if any CNS-related symptoms arise. The proactive counsel- Gastrointestinal Effects ing of patients on how to manage adverse events, as well as Gastrointestinal side effects such as constipation and diarrhea pre-emptive monitoring and treatment, is an integral compo- occurred in 14.2% and 17.6% of patients treated with lorlati- nent of patient care when initiating lorlatinib or any new treat- nib 100 mg QD, respectively, and were predominantly mild in ment regimen. Other adverse drug reactions with lorlatinib are severity. No grade ≥3 constipation adverse events were primarilymildtomoderateinseverityand canalsobeeffectively reported, and only two patients (0.7%) experienced grade managed with dose modifications and/or standard supportive 3diarrhea. Dose modifications were rarely required, and no medical therapy. patients discontinued lorlatinib as a result of gastrointestinal adverse events. General guidance should be followed in more CONCLUSION severe cases (Table 6), and constipation and diarrhea can be Lorlatinib has a unique safety profile to be considered when pre- managed with standard medical therapy. scribed for the treatment of patients with ALK-positive, metastatic, www.TheOncologist.com © AlphaMed Press 2019 Downloaded from https://academic.oup.com/oncolo/article/24/8/1103/6439309 by DeepDyve user on 01 February 2022 1110 Management of Adverse Events with Lorlatinib Manuscript writing: Todd M. Bauer, Enriqueta Felip, Benjamin J. Solomon, advanced NSCLC previously treated with a second-generation Holger Thurm, Gerson Peltz, Marc D. Chioda, Alice T. Shaw ALK TKI. A phase III study comparing lorlatinib with crizotinib in Final approval of manuscript: Todd M. Bauer, Enriqueta Felip, Benjamin treatment-naïve, ALK-positive, advanced NSCLC is underway. J. Solomon, Holger Thurm, Gerson Peltz, Marc D. Chioda, Alice T. Shaw ACKNOWLEDGMENTS DISCLOSURES Medical writing support was provided by Jade Drummond and Todd M. Bauer: Guardant Health, Ignyta, Loxo, Moderna Therapeutics, Pfizer (C/A); Enriqueta Felip: Celgene, Eli Lilly, Brian Szente of inScience Communications, Springer Health- Guardant Health, Takeda, AstraZeneca, Boehringer Ingelheim, care (Chester, U.K., and Philadelphia, PA), and was funded by Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Pfizer, Pfizer Inc. We thank Leonard P. James, formerly of Pfizer Inc., Roche (C/A), AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Pfizer, Roche (H); for insightful discussion and review of the manuscript. Benjamin J. Solomon: AstraZeneca, Eisai (C/A), AstraZeneca, Bristol-Myers Squibb, Merck, Novartis, Roche (other: travel expenses), Biodesix (VeriStrat) (IP), AstraZeneca, Bristol-Myers AUTHOR CONTRIBUTIONS Squibb (H); Holger Thurm: Pfizer (E, OI); Gerson Peltz: Pfizer (E, Conception/design: Todd M. Bauer, Enriqueta Felip, Benjamin J. Solomon, OI); Marc D. Chioda: Pfizer (E, OI); Alice T. Shaw: Ariad, Blueprint Holger Thurm, Gerson Peltz, Marc D. Chioda, Alice T. Shaw Medicines, Daiichi Sankyo, EMD Serono, Genentech, Ignyta, KSQ Provision of study material or patients: Todd M. Bauer, Enriqueta Felip, Therapeutics, Natera, Novartis, Pfizer, Roche and Taiho Benjamin J. Solomon, Alice T. Shaw Pharmaceutical (C/A), Novartis, Pfizer, Roche/Genentech (RF), Collection and/or assembly of data: Todd M. Bauer, Enriqueta Felip, Benjamin Novartis, Pfizer, Roche/Genentech, Foundation Medicine (H). J. Solomon, Holger Thurm, Gerson Peltz, Marc D. Chioda, Alice T. Shaw (C/A) Consulting/advisory relationship; (RF) Research funding; (E) Employment; (ET) Expert Data analysis and interpretation: Todd M. Bauer, Enriqueta Felip, Benjamin testimony; (H) Honoraria received; (OI) Ownership interests; (IP) Intellectual property J. Solomon, Holger Thurm, Gerson Peltz, Marc D. Chioda, Alice T. Shaw rights/inventor/patent holder; (SAB) Scientific advisory board REFERENCES 1. Koivunen JP, Mermel C, Zejnullahu K et al. lung cancer: A single-group, multicentre, phase resistance to first and second generation ALK EML4-ALK fusion gene and efficacy of an ALK 2 trial. Lancet Oncol 2016;17:234–242. inhibitors in preclinical models. Cancer Cell 2015; kinase inhibitor in lung cancer. Clin Cancer Res 28:70–81. 11. Shaw AT, Kim DW, Mehra R et al. Ceritinib 2008;14:4275–4283. in ALK-rearranged non-small-cell lung cancer. N 19. Shaw AT, Felip E, Bauer TM et al. Lorlatinib 2. Kris MG, Johnson BE, Berry LD et al. Using Engl J Med 2014;370:1189–1197. in non-small-cell lung cancer with ALK or ROS1 multiplexed assays of oncogenic drivers in lung rearrangement: An international, multicentre, open- 12. Gainor JF, Dardaei L, Yoda S et al. Molecular cancers to select targeted drugs. JAMA 2014; label, single-arm first-in-man phase 1 trial. Lancet mechanisms of resistance to first- and second- 311:1998–2006. Oncol 2017;18:1590–1599. generation ALK inhibitors in ALK-rearranged lung 3. Takeuchi K, Choi YL, Soda M et al. Multiplex cancer. Cancer Discov 2016;6:1118–1133. 20. Solomon BJ, Shaw AT, Ou S-HI et al. Phase reverse transcription-PCR screening for EML4- 2 study of lorlatinib in patients with advanced 13. Novello S, Mazieres J, Oh IJ et al. Primary ALK fusion transcripts. Clin Cancer Res 2008;14: ALK+/ROS1+ non-small-cell lung cancer. Paper results from the phase III ALUR study of alectinib 6618–6624. presented at: International Association for the Study versus chemotherapy in previously treated ALK+ of Lung Cancer 18th World Conference on Lung Can- 4. Takeuchi K, Soda M, Togashi Y et al. RET, non-small-cell lung cancer (NSCLC). Ann Oncol cer; October 15–18, 2017; Yokohama, Japan. ROS1 and ALK fusions in lung cancer. Nat Med 2017;28(suppl 5):1299O_PRa. 2012;18:378–381. 21. Solomon BJ, Besse B, Bauer TM et al. Lorla- 14. Shaw AT, Kim DW, Nakagawa K et al. Crizoti- tinib in patients with ALK-positive non-small-cell 5. Solomon BJ, Mok T, Kim DW et al. First-line nib versus chemotherapy in advanced ALK-positive lung cancer: Results from a global phase 2 study. crizotinib versus chemotherapy in ALK-positive lung cancer. N Engl J Med 2013;368:2385–2394. Lancet Oncol 2018;19:1654–1667. lung cancer. N Engl J Med 2014;371:2167–2177. 15. Shaw AT, Kim TM, Crino L et al. Ceritinib 22. Neuvonen PJ, Niemi M, Backman JT. Drug 6. Kim DW, Tiseo M, Ahn MJ et al. Brigatinib in versus chemotherapy in patients with ALK- interactions with lipid-lowering drugs: Mecha- patients with crizotinib-refractory anaplastic lym- rearranged non-small-cell lung cancer previously nisms and clinical relevance. Clin Pharmacol Ther phoma kinase-positive non-small-cell lung can- given chemotherapy and crizotinib (ASCEND-5): A 2006;80:565–581. cer: A randomized, multicenter phase II trial. randomised, controlled, open-label, phase 3 trial. J Clin Oncol 2017;35:2490–2498. 23. Reiner Z, Catapano AL, De Backer G et al. Lancet Oncol 2017;18:874–886. ESC/EAS guidelines for the management of dysli- 7. Peters S, Camidge DR, Shaw AT et al. Alecti- 16. Johnson TW, Richardson PF, Bailey S et al. pidaemias: The task force for the management of nib versus crizotinib in untreated ALK-positive Discovery of (10R)-7-amino-12-fluoro-2,10,16-tri- dyslipidaemias of the European Society of Cardiol- non-small-cell lung cancer. N Engl J Med 2017; methyl-15-oxo-10,15,16,17-tetrahydro-2h-8,4-(m ogy (ESC) and the European Atherosclerosis Soci- 377:829–838. etheno)pyrazolo[4,3-h][2,5,11]-benzoxadiazacy- ety (EAS). Eur Heart J 2011;32:1769–1818. clotetradecine-3-carbonitrile (PF-06463922), a macrocyclic 8. Soria JC, Tan DSW, Chiari R, et al. First-line 24. Niaspan (niacin extended-release): U.S. pre- inhibitor of anaplastic lymphoma kinase (ALK) and ceritinib versus platinum-based chemotherapy in scribing information. North Chicago, IL: Abbvie Inc., c-ros oncogene 1 (ROS1) with preclinical brain advanced ALK-rearranged non-small-cell lung can- exposure and broad-spectrum potency against cer (ASCEND-4): A randomised, open-label, phase ALK-resistant mutations. J Med Chem 2014;57: 3 study. Lancet 2017;389:917–929. 25. Fenoglide (fenofibrate): U.S. prescribing infor- 4720–4744. mation. San Diego, CA: Santarus, Inc.; 2012. 9. Katayama R, Shaw AT, Khan TM et al. Mech- 17. Schinkel AH. P-glycoprotein, a gatekeeper anisms of acquired crizotinib resistance in ALK- 26. Lovaza (omega-3-acid ethyl esters): U.S. in the blood-brain barrier. Adv Drug Deliv Rev rearranged lung cancers. Sci Transl Med 2012;4: prescribing information. Research Triangle Park, 1999;36:179-194. 120ra117. NC: GlaxoSmithKline, 2015. 10. Shaw AT, Gandhi L, Gadgeel S et al. Alectinib 18. Zou HY, Friboulet L, Kodack DP et al. PF- 27. Lopid (gemfibrozil): Summary of product char- in ALK-positive, crizotinib-resistant, non-small-cell 06463922, an ALK/ROS1 inhibitor, overcomes acteristics. Kent, U.K.: Pfizer Ltd, 2016. See http://www.TheOncologist.com for supplemental material available online. © AlphaMed Press 2019 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png The Oncologist Oxford University Press

Clinical Management of Adverse Events Associated with Lorlatinib

Loading next page...
 
/lp/oxford-university-press/clinical-management-of-adverse-events-associated-with-lorlatinib-vEkJCPeC0b

References (27)

Publisher
Oxford University Press
Copyright
Copyright © 2022 Oxford University Press
ISSN
1083-7159
eISSN
1549-490X
DOI
10.1634/theoncologist.2018-0380
Publisher site
See Article on Publisher Site

Abstract

Downloaded from https://academic.oup.com/oncolo/article/24/8/1103/6439309 by DeepDyve user on 01 February 2022 Lung Cancer Clinical Management of Adverse Events Associated with Lorlatinib a b c d e f g TODD M. BAUER, ENRIQUETA FELIP, BENJAMIN J. SOLOMON, HOLGER THURM, GERSON PELTZ, MARC D. CHIODA, ALICE T. SHAW a b Sarah Cannon Cancer Research Institute/Tennessee Oncology, PLLC, Nashville, Tennessee, USA; Vall d’Hebron University Hospital, c d Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain; Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia; Pfizer e f Oncology, La Jolla, California, USA; Pfizer Oncology, Groton, Connecticut, USA; Pfizer Oncology, New York, New York, USA; Massachusetts General Hospital, Boston, Massachusetts, USA Disclosures of potential conflicts of interest may be found at the end of this article. Key Words. Lorlatinib � Non-small cell lung cancer � Safety � Drug therapy management ABSTRACT Lorlatinib is a novel, highly potent, brain-penetrant, third- agent. Prescription of supportive therapy should also con- generation ALK/ROS1 tyrosine kinase inhibitor (TKI), which sider the potential for drug-drug interactions with lorlatinib has broad-spectrum potency against most known resistance via engagement of specific CYP450 enzymes. This article sum- mutations that can develop during treatment with crizotinib marizes the clinical experience from lorlatinib phase I investi- and second-generation ALK TKIs. The safety profile of lorlati- gators and was generated from discussion and review of the nib was established based on 295 patients who had received clinical study protocol and database to provide an expert the recommended dose of lorlatinib 100 mg once daily. consensus opinion on the management of the key adverse Adverse events associated with lorlatinib are primarily mild reactions reported with lorlatinib, including hyperlipidemia, to moderate in severity, with hypercholesterolemia (82.4%), central nervous system effects, weight increase, edema, periph- hypertriglyceridemia (60.7%), edema (51.2%), peripheral eral neuropathy, and gastrointestinal effects. Overall, lorlatinib neuropathy (43.7%), and central nervous system effects 100 mg once daily has a unique safety profile to be consid- (39.7%) among the most frequently reported. These can be ered when prescribed, based on the recent U.S. Food and effectively managed with dose modification and/or standard Drug Administration approval, for the treatment of patients supportive medical therapy, as indicated by a low incidence with ALK-positive metastatic non-small cell lung cancer previ- of permanent discontinuations due to adverse reactions. ously treated with a second-generation ALK TKI. The Oncologist Most patients (81.0%) received at least one lipid-lowering 2019;24:1103–1110 Implications for Practice: Despite the advancement of second-generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs), the emergence of resistance and progression of central nervous system metastases remain clinically significant problems in ALK-positive non-small cell lung cancer. Lorlatinib is a potent, brain-penetrant, third-generation, macrocyclic ALK/ROS1 TKI, with broad-spectrum potency against most known resistance mutations that can develop during treatment with existing first- and second-generation ALK TKIs. This article provides recommendations for the clinical man- agement of key adverse reactions reported with lorlatinib. BACKGROUND Rearrangements of the anaplastic lymphoma kinase (ALK) of acquired (or secondary) resistance that occurs through gene are found in 3%–5% of patients with non-small cell lung several molecular mechanisms, including development of sec- cancer (NSCLC) [1–4] and represent a clinically and molecu- ondary mutations within the ALK kinase domain and activation larly distinct subtype of NSCLC. Standard therapy for patients of alternative signaling pathways [9]. More potent second- with ALK-positive NSCLC includes crizotinib, a multitargeted generation ALK TKIs were developed to surmount the develop- ALK/ROS1/MET tyrosine kinase inhibitor (TKI) [5] and, more ment of crizotinib resistance in ALK-positive NSCLC and have recently, second-generation ALK TKIs [6–8]. However, most demonstrated improved response rates in crizotinib-refractory patients treated with crizotinib relapse over time because and treatment-naïve patients [7, 8, 10, 11]. However, most Correspondence: Todd M. Bauer, M.D., Sarah Cannon Cancer Research Institute/Tennessee Oncology, PLLC, 250 25th Ave. N, Nashville, Tennessee 37203, USA. Telephone: 1-615-329-7274; e-mail: tbauer@tnonc.com Received June 27, 2018; accepted for publication February 15, 2019; published Online First on March 19, 2019. http://dx.doi.org/10.1634/theoncologist.2018-0380 The Oncologist 2019;24:1103–1110 www.TheOncologist.com © AlphaMed Press 2019 Downloaded from https://academic.oup.com/oncolo/article/24/8/1103/6439309 by DeepDyve user on 01 February 2022 1104 Management of Adverse Events with Lorlatinib patients will eventually develop resistance to second-generation based on prior treatment and rearrangement status (expansion ALK TKIs [12]. cohorts 1–5, ALK-positive; expansion cohort 6, ROS1-positive), details of which have been previously presented [21]. In April Treatment options following the emergence of resistance to a second-generation ALK TKI are limited, with platinum- 2017, lorlatinib was granted breakthrough therapy designation by the U.S. Food and Drug Administration (FDA) in patients based chemotherapy as the current standard of care. How- ever, the associated toxicities, consisting of adverse events with ALK-positive advanced NSCLC previously treated with one or more ALK inhibitors and, in November 2018, the FDA such as nausea, vomiting, and neutropenia, can negatively impact patients’ quality of life. Although there are no pub- granted lorlatinib an accelerated approval for the treatment of patients with ALK-positive metastatic NSCLC who had dis- lished data on the antitumor activity of chemotherapy after second-generation ALK TKIs, response rates of 27%–45% have ease progression on crizotinib and at least one other ALK TKIorwho haddisease progressiononalectinib or ceritinib as been reported with platinum- and pemetrexed-based chemo- therapy in the first-line treatment of ALK-positive advanced the first ALK TKI. The phase III CROWN study (NCT03052608) comparing lorlatinib with crizotinib as first-line treatment NSCLC [5, 8], and response rates ranging from 7% to 11% have been reported with single-agent chemotherapy in among patients with ALK-positive advanced NSCLC is currently enrolling patients. patients previously treated with a platinum doublet and crizotinib [13–15]. Lorlatinib is a novel, highly potent, third-generation, macro- cyclic ALK/ROS1 TKI that competitively binds to the adenosine LORLATINIB:SAFETY AND TOLERABILITY triphosphate-binding pocket, blocking ALK-dependent onco- genic signaling. Lorlatinib was also designed to penetrate the Overview The safety profile of lorlatinib was established based on blood–brain barrier in part by minimizing p-glycoprotein- 1-mediated efflux, which can lead to poor blood–brain barrier 295 patients who had received the recommended dose of lorlatinib 100 mg once daily (QD) in the fully recruited, penetration [16, 17]. Lorlatinib has broad-spectrum potency against most known resistance mutations that can develop ongoing phase I/II study (NCT01970865). This pooled group comprised 17 patients from the phase I portion of the during treatment with crizotinib and second-generation ALK TKIs, including the difficult-to-treat ALK G1202R mutation [18]. study, 275 patients from the phase II portion, and 3 patients from a Japanese lead-in cohort—an evaluation study of the safety and tolerability of lorlatinib in Japanese patients LORLATINIB:PHARMACOLOGY conducted before sites in Japan could participate in the In preclinical studies, advantageous pharmacokinetic proper- phase II study because of lack of documented experience ties have been reported for lorlatinib including low plasma in this patient population. The data presented in this article clearance, 100% oral bioavailability, and a moderate volume are based on a cutoff date of March 15, 2017. of distribution [16]. Lorlatinib may be taken with or without The incidence and management of the most frequent food and is rapidly absorbed (peak plasma concentrations adverse reactions (i.e., adverse drug reactions) with lorlatinib, occurring 1–2 hours after dosing), with a terminal elimination particularly those occurring in ≥10% of patients, are reported. half-life of 19.0–28.8 hours (Pfizer, data on file). The high Adverse drug reactions are defined as those adverse events blood–brain barrier penetration of lorlatinib is supported by a that, after internal clinical and safety review applying medical mean ratio of cerebrospinal fluid/plasma (unbound) of 0.75 judgment, were determined to be likely associated with the [19]. Lorlatinib is metabolized primarily by cytochrome P450 study treatment. This is in contrast to the broad category of (CYP)3A, CYP2C19, and CYP2C8 and uridine 5’-diphospho- all-causality adverse events, which may or may not have an glucuronosyltransferase and has also exhibited time-dependent established causal relationship. It is further important to note inhibition of CYP3A4/5 as well as induction of CYP2B6 and that the definitions and reporting thresholds for adverse reac- CYP3A4 (Pfizer, data on file). Thus, lorlatinib may have the tions can vary across different regulatory health authorities, potential to alter the pharmacokinetics of other coadministered and in certain circumstances, these concepts can be used drugs that are metabolized by CYP2B6 or CYP3A. A phase I, interchangeably. In the phase I/II study (based on the data open-label, crossover study (ClinicalTrials.gov identifier: cutoff of March 15, 2017), adverse reactions consisted of NCT02804399) found that concomitant administration of lor- adverse events including hypercholesterolemia, hypertri- latiniband rifampin ledtoelevatedaspartate andalanine ami- glyceridemia, central nervous system (CNS) effects (mood notransferase levels (Pfizer, data on file). Therefore, the use of disorder, cognitive disorder, and speech disorder), weight strong CYP3A4/5 inducers with lorlatinib is contraindicated. increase, edema, peripheral neuropathy, diarrhea, constipa- tion, fatigue, arthralgia, and vision disorder. Additional adverse events of clinical interest included lipase increase and atrio- LORLATINIB:CLINICAL EXPERIENCE ventricular (AV) block. In an ongoing phase I/II study (NCT01970865), lorlatinib dem- Adverse reactions in this pooled safety analysis population onstrated clinically meaningful benefit, including substantial of 295 patients treated with lorlatinib 100 mg QD are shown intracranial efficacy, among patients with ALK-positive or in Table 1. Hyperlipidemia, edema, and peripheral neuropathy ROS1-positive advanced NSCLC who were treatment naïve were among the most frequently reported adverse reactions or who had received a range of prior ALK inhibitors with or with lorlatinib treatment. Most adverse reactions were grade without chemotherapies [19, 20]. Patients in the phase II 1 or 2 in severity, with few grade ≥ 3 adverse reactions reported portion of this study were enrolled into six expansion cohorts (Table 1). Serious adverse reactions occurred in 9 patients © AlphaMed Press 2019 Downloaded from https://academic.oup.com/oncolo/article/24/8/1103/6439309 by DeepDyve user on 01 February 2022 Bauer, Felip, Solomon et al. 1105 Table 1. Adverse reactions in ≥10% of all patients or Grade dose delay (3.4% and 4.7%, respectively) or dose reduction ≥3 adverse reactions in any patient treated with lorlatinib (0.7% and 1.7%, respectively) and did not result in any per- 100 mg once daily manent discontinuations across the study. In most cases, these typically asymptomatic adverse events were easily man- Pooled lorlatinib 100 mg aged with appropriate medical therapy (i.e., lipid-lowering once daily (N = 295) Adverse drug agents) and dose interruptions, coupled with dose modifica- reactions, n (%) All grades Grade 3 Grade 4 tions for more severe (grade ≥3) and difficult-to-treat adverse Hypercholesterolemia 243 (82.4) 41 (13.9) 5 (1.7) events (Table 2). Hypertriglyceridemia 179 (60.7) 39 (13.2) 7 (2.4) Most patients (81.0%) received at least one lipid-lowering Edema 151 (51.2) 7 (2.4) 0 (0.0) agent and commenced treatment within 3 weeks of the first lor- Peripheral neuropathy 129 (43.7) 7 (2.4) 0 (0.0) latinib dose (median time to start of lipid-lowering medication, 20 days [range, 1–190]). Among 226 patients who received a Cognitive effects 68 (23.1) 5 (1.7) 0 (0.0) lipid-lowering agent for hypercholesterolemia and 198 who Fatigue 68 (23.1) 1 (0.3) 0 (0.0) received a lipid-lowering agent for hypertriglyceridemia, 22.1% Mood effects 62 (21.0) 4 (1.4) 0 (0.0) and 30.8% of patients required the addition of another lipid- Weight increase 61 (20.7) 7 (2.4) 0 (0.0) lowering agent, respectively. The most commonly prescribed Arthralgia 58 (19.7) 0 (0.0) 0 (0.0) lipid-lowering agent was rosuvastatin (n =124; 42.0% of Diarrhea 52 (17.6) 2 (0.7) 0 (0.0) patients). Treatment with a statin is recommended at the first sign of elevated cholesterol (upper limit of normal, Constipation 42 (14.2) 0 (0.0) 0 (0.0) 300 mg/dL [upper limit of normal, 7.75 mmol/L]) and/or tri- Vision disorder 39 (13.2) 1 (0.3) 0 (0.0) glyceride levels (150–300 mg/dL [1.71–3.42 mmol/L]). The Speech effects 28 (9.5) 1 (0.3) 0 (0.0) choice and dosing of statins may be guided by information Clustered term comprising adverse events that represent similar on the differential metabolism by the CYP450 pathway (sup- clinical symptoms/syndromes. plemental online Table 1). Pitavastatin, pravastatin, or rosu- Based on Common Terminology Criteria for Adverse Events (v4.03). vastatin should initially be considered based on their low involvement with specific CYP450 enzymes that can interact (3.0%), and the most frequently reported were cognitive disor- with lorlatinib (e.g., CYP3A4) [22]. The addition of fibrates or der (1.0%) and edema (0.7%). fish oils is considered effective in lowering triglyceride levels Temporary dose interruptions and dose reductions asso- if treatment beyond statins is required [23]. Of these, fenofi- ciated with adverse reactions were reported in 21.7% and brate can be administered first as it has the least involvement 19.7% of patients, respectively. The most common cause for with the associated CYP450 enzymes, followed by fish oils dose interruptions and dose modifications was edema (5.8% and nicotinic acid [24–26]. Of note, the concomitant use of and 6.1% of patients, respectively). Overall, the incidence gemfibrozil and some statins is not recommended. In partic- of permanent discontinuations due to adverse reactions ular, coadministration of gemfibrozil with simvastatin is con- was low (n = 6 [2.0%]). The adverse reactions that led to traindicated [27]. Ezetimibe may also be considered if treatment permanent treatment discontinuations were cognitive dis- with statins and fenofibrate is ineffective. order (n = 2), mood disorder (n = 2), edema (n =1), and Dose interruptions are recommended if cholesterol fatigue (n =1). levels reach >500 mg/dL and/or triglyceride levels reach This article summarizes the clinical experience from lorla- >1,000 mg/dL despite the use of lipid-lowering therapies. tinib phase I investigators and was generated from discus- Lorlatinib should be withheld, while maximizing lipid-lowering sion and review of the clinical study protocol and database treatment, until severity is reduced before rechallenging at to provide an expert consensus opinion on the management the same dose. Reducing the lorlatinib dose is suggested only of the key adverse reactions reported with lorlatinib, includ- if cholesterol levels >500 mg/dL and/or triglyceride levels ing hyperlipidemia, CNS effects, weight increase, edema, >1,000 mg/dL recur (Table 2). peripheral neuropathy and gastrointestinal effects. Lipase In light of the frequent occurrence of hyperlipidemia, increase and AV block adverse events are also discussed. patients should be informed of the likelihood of requiring lipid-lowering therapy or that an increase in dose may be neces- Management of Specific Adverse Events sary for those patients already receiving lipid-lowering agents. Hyperlipidemia In addition, patients should be aware that monitoring of serum Hyperlipidemia, comprising the cluster terms hypercholesterol- cholesterol and triglyceride levels is to be expected before and emia and hypertriglyceridemia, was the most common adverse throughout the course of treatment with lorlatinib (supplemen- reaction reported with lorlatinib and usually occurred within tal online Table 2). However, patients should be advised that the first few weeks of treatment (median time to onset, hyperlipidemia associated with lorlatinib treatment is easily 15 days [range, 1–219]; supplemental online Fig. 1). Hypercho- managed and resolvable through lipid-lowering therapy and/or lesterolemia and hypertriglyceridemia were reported in 82.4% dose modifications. and 60.7% of patients in the pooled safety group, respectively, and both events were mostly grade 1 or 2 in severity. Grade 3/4 CNS Effects hypercholesterolemia and hypertriglyceridemia both occurred A broad spectrum of CNS effects can occur in patients at a frequency of 15.6%. However, hypercholesterolemia receiving lorlatinib, and the following section summarizes and hypertriglyceridemia were not common reasons for the changes in cognitive function, mood, and speech that www.TheOncologist.com © AlphaMed Press 2019 Downloaded from https://academic.oup.com/oncolo/article/24/8/1103/6439309 by DeepDyve user on 01 February 2022 1106 Management of Adverse Events with Lorlatinib Table 2. Dose modification guidelines for lorlatinib-related hyperlipidemias by severity Severity Guidance Mild: � Introduce or modify lipid-lowering therapy Cholesterol ULN–300 mg/dL � Continue at the same lorlatinib dose OR Triglycerides 150–300 mg/dL Moderate: Cholesterol >300–400 mg/dL OR Triglycerides >300–500 mg/dL Severe: � Introduce lipid-lowering agent or increase dosage of ongoing lipid-lowering Cholesterol >400–500 mg/dL therapy, or change to a new lipid-lowering therapy OR � Continue at the same lorlatinib dose without interruption Triglycerides >500–1,000 mg/dL Life threatening: � Introduce lipid-lowering agent or increase dosage of ongoing lipid-lowering Cholesterol >500 mg/dL therapy, or change to a new lipid-lowering therapy OR � Withhold lorlatinib dose until hyperlipidemia is moderate or mild before Triglycerides >1000 mg/dL rechallenging at same dose while maximizing lipid-lowering therapy � If severe hyperlipidemia recurs despite maximal lipid-lowering therapy, reduce lorlatinib dose by one dose level (by 25 mg) Abbreviation: ULN, upper limit of normal. Table 3. Dose modification guidelines for lorlatinib-related 2 or 3 CNS adverse events, lorlatinib should be withheld until central nervous system effects by CTCAE grade recovery to grade ≤1 before rechallenging at a reduced dose. Permanent discontinuation from lorlatinib is recommended CTCAE grade Guidance for grade 4 CNS effects. In addition, patients and their caregivers Grade 1: Mild � Continue at the same should be instructed to report any changes in cognitive function, dose or withhold dose mood, or speech to their health care provider. until recovery to baseline � Rechallenge at the same dose or reduce dose by Mood Effects. Behavioral alterations and mood changes asso- one dose level (by 25 mg) ciated with lorlatinib in clinical studies were collected under Grade 2: Moderate � Withhold dose until OR adverse event is grade ≤1 the cluster term “mood effects” and are showninTable 4. Grade 3: Severe � Rechallenge at one These effects occurred at a frequency of 21.0%, with a median reduced dose level time to onset of 43 days (range, 1–452 days). Irritability, anxi- (by 25 mg) Grade 4: Life-threatening/ � Permanently discontinue ety, depression, and affect lability were the most common urgent intervention indicated lorlatinib mood adverse events reported. Mood changes observed with Based on CTCAE (v4.03). lorlatinib were mostly mild in severity (19.7%), with no grade Abbreviation: CTCAE, Common Terminology Criteria for Adverse Events. 4 adverse events reported. The overall frequency of mood effects was comparable between patients <65 years of age have been reported in patients receiving lorlatinib. These (21.6%) and those ≥65 years (18.5%); however, they were adverse reactions were reported at a frequency of 39.7%, reported more frequently in non-Asian (27.3%) compared with with 11.9% of patients experiencing more than one type of Asian patients (10.2%). Most patients with mood effects will CNS effect (supplemental online Fig. 2). Baseline CNS metas- describe feeling more irritable, more prone to impatience or tases were present in 84 (71.8%) of 117 patients with CNS anger, or sometimes more anxious. When patients first start effects (supplemental online Fig. 3). Of the 84 patients with treatment, some report feeling a little “energized” or even CNS effects and baseline CNS metastases, 22 (26.2%) had “buzzed.” Patients have also reported “feeling flat” and/or received prior whole-brain radiation therapy (supplemental “feeling less excited about things.” Additional assessments of online Fig. 4). CNS adverse reactions were generally mild in mood and suicidal ideation and behavior were a requirement severity and intermittent and improved or resolved upon of the phase II study and were administered to patients at the dose modifications. Out of 117 patients who experienced beginning of each cycle up to cycle 6 and then every other CNS effects, 24 required ≥1dose modification (temporary cycle thereafter. Based on the phase II portion (n = 275), there discontinuation and/or dose reduction), with 15 (62.5%) of were no trends in the Beck Depression Inventory-II summary these patients experiencing resolution of their CNS effects. data to suggest worsening of symptoms during treatment with The median time to resolution of CNS effects was 12.5 days lorlatinib. Likewise, there were no trends in the Columbia- (range 2–112). Recurrence of CNS effects upon rechallenge Suicide Severity Rating Scale group summary data to suggest a at the same and reduced dose occurred in six (25.0%) and notable shift in suicidal ideation or behavior during treatment seven (29.2%) patients, respectively. General dose modifica- with lorlatinib (Pfizer, data on file). Mood effects related to lor- tion guidelines appropriate for any of the CNS effects are latinib were associated with dose interruptions and reductions outlined in Table 3. Dose interruptions should be considered in eight (2.7%) and seven (2.4%) patients, respectively. Out of in the presence of grade 1 CNS effects and enforced until the 12 mood events that required dose modification (i.e., dose recovery to baseline before restarting lorlatinib at the same reduction, temporary discontinuation, or both), 8 (66.7%) dose or, if required, at a lower dose. For patients with grade events resolved. The median time to resolution was 14 days © AlphaMed Press 2019 Downloaded from https://academic.oup.com/oncolo/article/24/8/1103/6439309 by DeepDyve user on 01 February 2022 Bauer, Felip, Solomon et al. 1107 Table 4. Mood disorder adverse events with lorlatinib Table 5. Cognitive disorder adverse events with lorlatinib Pooled lorlatinib 100 mg Pooled lorlatinib 100 mg once daily (N = 295) once daily (N = 295) Preferred term, n (%) All grades Grade 3 Grade 4 Preferred term, n (%) All grades Grade 3 Grade 4 Any adverse event 62 (21.0) 4 (1.4) 0 (0.0) Any adverse event 68 (23.1) 5 (1.7) 0 (0.0) Irritability 18 (6.1) 2 (0.7) 0 (0.0) Memory impairment 26 (8.8) 0 (0.0) 0 (0.0) Anxiety 15 (5.1) 1 (0.3) 0 (0.0) Cognitive disorder 18 (6.1) 2 (0.7) 0 (0.0) Depression 12 (4.1) 1 (0.3) 0 (0.0) Amnesia 16 (5.4) 0 (0.0) 0 (0.0) Affect lability 7 (2.4) 0 (0.0) 0 (0.0) Confusional state 11 (3.7) 2 (0.7) 0 (0.0) Personality change 5 (1.7) 0 (0.0) 0 (0.0) Disturbance in attention 7 (2.4) 0 (0.0) 0 (0.0) Mood swings 3 (1.0) 0 (0.0) 0 (0.0) Delirium 2 (0.7) 1 (0.3) 0 (0.0) Affective disorder 2 (0.7) 0 (0.0) 0 (0.0) Mental impairment 2 (0.7) 0 (0.0) 0 (0.0) Aggression 2 (0.7) 0 (0.0) 0 (0.0) Attention deficit/hyperactivity 1 (0.3) 0 (0.0) 0 (0.0) disorder Agitation 2 (0.7) 1 (0.3) 0 (0.0) Dementia 1 (0.3) 0 (0.0) 0 (0.0) Mood altered 2 (0.7) 0 (0.0) 0 (0.0) Reading disorder 1 (0.3) 0 (0.0) 0 (0.0) Depressed mood 1 (0.3) 0 (0.0) 0 (0.0) Based on Common Terminology Criteria for Adverse Events (v4.03). Euphoric mood 1 (0.3) 0 (0.0) 0 (0.0) Mania 1 (0.3) 0 (0.0) 0 (0.0) analysis, there was little evidence of any systematic decline in Based on Common Terminology Criteria for Adverse Events (v4.03). cognition associated with lorlatinib (Pfizer, data on file). Cognitive effects were among the most frequently reported adverse events (range 2–112). Recurrence upon rechallenge at a reduced associated with dose interruptions (3.7%) and dose reductions dose was reported with four (33.3%) mood events; no recur- (2.7%). Out of the 33 cognitive effects that required dose rence following rechallenge at the same dose was reported. modification(s), 22 (66.7%) resolved. The median time to reso- Affect lability and anxiety resulted in permanent treatment lution was 10 days (range, 3–39). Seven (21.2%) cognitive discontinuation in one patient each. effects recurred upon rechallenge with the same dose of lor- Effects on mood should be discussed with patients latinib and four (12.1%) recurred with a reduced dose. Two before lorlatinib is administered. It is particularly important patients permanently discontinued lorlatinib as a result of cog- to review these effects with patients who have pre-existing nitive disorder (n = 1) and confusional state (n =1). psychiatric conditions. Caregivers and family members, as The possibility of cognitive-related adverse reactions should well as patients, should also be encouraged to report any be discussed with patients and caregivers before starting lorlati- changes in patients’ mood during treatment with lorlatinib nib treatment, along with advice on how to minimize the in the event that patients are unaware of such changes. impact on daily activities (e.g., setting reminders). Patients These adverse events are temporary and reversible upon should be advised to inform their health care provider if they dose interruption or reduction. experience any changes in cognitive functioning. As with all CNS effects, dose modifications, imposed at low thresholds, are generally effective in reversing these adverse events (Table 3), Cognitive Effects. Cognitive effects (cluster term) were re- and the importance of dose reduction should be emphasized if ported in 23.1% of patients treated with lorlatinib in the patients’ usual activities or relationships are impaired by cogni- pooled safety analysis. These adverse events, which most tive or mood effects. commonly included memory impairment, cognitive disorder, and amnesia, usually presented within the first 2 months of treatment (median time to onset, 53 days [range, 1–423]) Speech Effects. Speech effects (cluster term) occurred in and were mainly grade ≤ 2 in severity (21.4%; Table 5). The 9.5% of patients, with a median time to onset of 42 days frequency of cognitive effects was comparable between age (range, 1–404). Dysarthria, slow speech, and speech disorder groups (<65 years [22.4%] or ≥ 65 years [25.9%]); however, were reported in 3.7%, 3.4%, and 2.4% of patients, respec- they were reported at a higher frequency in non-Asian (28.0%) tively (supplemental online Table 3). Overall, these adverse compared with Asian patients (12.0%). Five grade 3 cognitive events were predominantly mild in severity (grade 1, 8.5%). effects were reported: cognitive disorder (n = 2), confusional One patient required a dose reduction and interruption as a state (n = 2), and delirium (n = 1). Patients have reported result of dysarthria. Of the three speech events that required experiences described as “sluggish thought,”“fogginess,” dose modification(s), two (66.7%) events resolved. The median “trouble connecting the dots,” difficulty multitasking, difficulty time to resolution was 38.5 days (range, 35–42). One (33.3%) finding the right words, issues with short-term memory or out of three speech events with dose modifications recurred recall, and confusion and hallucinations in severe cases. An upon rechallenge at the same dose of lorlatinib; no recurrence assessment of cognitive function, which tested verbal learning, was reported with rechallenge at a reduced dose. No patients psychomotor function, delayed recall, attention, and working permanently discontinued treatment because of speech effects. memory, was conducted in the phase II portion and validated Speech effects have been reported by patients as a percep- by a central vendor (Cogstate, Inc., New Haven, CT). From this tion of slowed speech or difficulty in word finding. Although www.TheOncologist.com © AlphaMed Press 2019 Downloaded from https://academic.oup.com/oncolo/article/24/8/1103/6439309 by DeepDyve user on 01 February 2022 1108 Management of Adverse Events with Lorlatinib the altered speech experienced is typically mild, the ability to Table 6. General dose modification guidelines for lorlatinib- tolerate such adverse events can vary between patients. related adverse reactions by CTCAE grade Therefore, patients should be counseled on the potential CTCAE grade Guidance for speech effects at the time of treatment initiation and Grade 1: Mild � Continue at the same dose or should be reassured that these adverse events are revers- OR reduce by one dose level ible following dose modifications or treatment cessation, if Grade 2: Moderate (by 25 mg) required. Patients should also notify their health care pro- Grade 3: Severe � Withhold dose until adverse vider if they experience any changes in their speech. OR event is grade ≤2 or returned Grade 4: Life-threatening/ to baseline (if not considered a urgent intervention safety risk for the patient) Weight Increase indicated � Rechallenge at one reduced Reports of weight increases among patients treated with lorlati- dose level (by 25 mg) nib usually presented within 2 months of treatment initiation Based on CTCAE (v4.03). (median time to onset, 64 days [range, 1–519]). Of 282 evalu- Permanent discontinuation is recommended if patient is unable to tolerate lorlatinib 50 mg taken orally once daily. able patients in the pooled safety group, 87 (30.9%) had a Abbreviation: CTCAE, Common Terminology Criteria for Adverse Events. 10%–20% increase of their baseline body weight and 38 (13.5%) had a >20% increase of their baseline body weight. The median of maximum percent change from base- management of edema. The addition of spironolactone can line was 11.4% (range, 0.2–55.2). However, weight increase also be beneficial in the treatment of edema refractory to furo- was only reported as an adverse event in 61 patients (20.7%), semide monotherapy. However, if edema persists or worsens, most of which were grade ≤2 in severity (18.3%). An increase general dose modification guidance can be used with lorlatinib in weight was reported as an adverse event in 4.1% of treatment and held until improvement to grade ≤2 (if not a patients at Cycle 1, 13.3% of patients by Cycle 4, and 23.4% of safety risk) or returned to baseline and rechallenged at a patients by Cycle 8. An increase in appetite has been reported reduced dose (Table 6). by some patients, suggesting that body weight increase may potentially be associated with increased caloric intake and a heightened desire to eat; however, causality has not been Peripheral Neuropathy determined. Additionally, cases of weight gain (≥10% increase Peripheral neuropathy (cluster term) associated with lorlati- from baseline) reported concurrently with edema were lim- nib was reported at a frequency of 43.7%, with a median ited and are shown in supplemental online Figure 5. time to onset of 77 days (range, 1–723). Within the cluster Two patients required dose interruptions and two required term, the most common adverse events reported were par- dose reductions as a result of weight increase associated esthesia (13.2%) and neuropathy peripheral (11.2%). Other with lorlatinib treatment. Although relatively uncommon, dose peripheral neuropathy adverse events seen with lorlatinib modifications (Table 6) should be applied in more severe cases included peripheral sensory neuropathy and muscular weak- of weight gain. ness (Table 7). In general, peripheral neuropathy adverse Food intake counseling, dietary advice from a nutrition- events were mild in severity (grade ≤2, 41.4%) and revers- ist, and the addition of exercise also appear to be effective ible following dose modifications or standard medical ther- weight management strategies, although nonadherence can apy. Symptoms were often described as tingling, numbness, be an issue. Patients should be advised from the outset that and pain at night in extremities (especially in patients experienc- they are likely to experience some degree of weight gain. ing symptoms similar to carpal tunnel syndrome). In patients This will ensure that patients are prepared and can expect with pre-existing carpal tunnel syndrome, symptoms often wors- to implement some lifestyle adjustments. ened when they received lorlatinib. Patients with peripheral neuropathy often also reported adverse events of weight gain Edema and/or edema (71.3%); overlap of these three adverse events is Treatment with lorlatinib was associated with edema (51.2%), shown in supplemental online Figure 6. with peripheral edema arising as the most frequently reported Peripheral neuropathy was among the most frequently event (41.7%). Other adverse events reported within the edema reported adverse events associated with dose interruptions cluster term were edema (7.5%), peripheral swelling (6.1%), (4.1%) and dose reductions (4.1%) but responded well to these generalized edema (0.7%), and swelling (0.7%). The median dose modifications. General guidance on dose modifications time to onset of edema was 42 days (range, 1–232), with a should be considered in higher-severity cases (Table 6). Thus, if median duration of 163 days. Most adverse events were mild grade ≥3 peripheral neuropathy occurs following administration in severity (grade ≤2, 48.8%), and only 2.4% of patients expe- of lorlatinib, treatment should be temporarily discontinued rienced grade 3 events. Edema was the most common cause until adverse events are reduced to grade ≤2(if nota safety of dose interruptions (5.8%) and dose reductions (6.1%) in the risk) or returned to baseline and the patient rechallenged at a pooled safety analysis group. reduced lorlatinib dose. Treatment with vitamin B and vitamin In practice, compression stockings, leg elevations, and life- B and medications for pain associated with peripheral style modifications, such as increased exercise and limiting neuropathy (e.g., gabapentin or pregabalin) may also pro- dietary salt, should initially be considered in patients with low- vide symptom relief in some cases. For carpal tunnel syn- grade edema before commencing with dose modifications. drome, the use of a night splint has been found to provide These conservative measures, in combination with diuretics improvement in some patients. However, in more signifi- (usually furosemide), have shown to be effective in the cant cases, patients may opt for release surgery. © AlphaMed Press 2019 Downloaded from https://academic.oup.com/oncolo/article/24/8/1103/6439309 by DeepDyve user on 01 February 2022 Bauer, Felip, Solomon et al. 1109 Table 7. Peripheral neuropathy adverse events with AV Block and Other Electrocardiogram Findings lorlatinib In a study of healthy volunteers who were administered lorla- tinib, analysis of electrocardiogram (ECG) data revealed some Pooled lorlatinib 100 mg evidence of PR prolongation, although no adverse events once daily (N = 295) associated with AV block were reported. However, of 295 Preferred term, N (%) All grades Grade 3 Grade 4 patients treated with lorlatinib, asymptomatic first-degree AV Any adverse event 129 (43.7) 7 (2.4) 0 (0.0) block (grade 1 in severity) was reported in 2 patients (0.7%). Paresthesia 39 (13.2) 1 (0.3) 0 (0.0) Complete AV block was reported for one patient (0.3%; grade 3) Neuropathy peripheral 33 (11.2) 2 (0.7) 0 (0.0) and led to temporary discontinuation from treatment, although Peripheral sensory neuropathy 25 (8.5) 1 (0.3) 0 (0.0) it should be noted that this patient had pre-existing second- degree AV block. There were no other dose modifications or dis- Muscular weakness 15 (5.1) 1 (0.3) 0 (0.0) continuations as a result of AV block. Gait disturbance 9 (3.1) 1 (0.3) 0 (0.0) ECG QT prolongation was reported in 19 patients (6.4%), Carpal tunnel syndrome 8 (2.7) 1 (0.3) 0 (0.0) most of which were grade ≤2, although one event was grade Hypoesthesia 8 (2.7) 0 (0.0) 0 (0.0) 3 in severity and required temporary discontinuation. None of Dysesthesia 5 (1.7) 0 (0.0) 0 (0.0) these events resulted in permanent treatment discontinuation. Before initiating treatment with lorlatinib, patients should be Neuralgia 3 (1.0) 1 (0.3) 0 (0.0) informed of the potential risks of AV block and advised to con- Neurotoxicity 3 (1.0) 0 (0.0) 0 (0.0) tact their health care provider immediately if they experience Burning sensation 1 (0.3) 0 (0.0) 0 (0.0) any new chest pain or discomfort, changes in heartbeat, palpi- Formication 1 (0.3) 0 (0.0) 0 (0.0) tations, dizziness, lightheadedness, or fainting, and changes in Sensory disturbance 1 (0.3) 0 (0.0) 0 (0.0) or new use of heart or blood pressure medication. For patients Based on Common Terminology Criteria for Adverse Events (v4.03). with pre-existing PR prolongation, ECG monitoring should be conducted throughout the course of treatment (supplemental In addition, peripheral neuropathy may be associated online Table 2). For patients who develop AV block, dose modi- with peripheral edema (primarily of the upper extremities). fication may be required depending upon the degree of AV In such instances, treatment with diuretics might improve block and whether the patient exhibits symptoms. Dose modi- peripheral neuropathy symptoms as well as reduce edema. fication guidelines for patients with AV block are described in supplemental online Table 4. Increase in Lipase SUMMARY In thepooledsafetyanalysisgroup,anincreaseinlipasewas Lorlatinib has an unique safety profile, distinct from those of reported as an adverse event in 10.8% of patients treated with other ALK TKIs, and is generally well tolerated with a low inci- lorlatinib. Of 290 evaluable patients, lipase increases were dence of permanent discontinuations due to adverse reac- reported as a laboratory abnormality (any grade) in 77 patients tions (n = 6 [2.0%]). Temporary dose interruptions and dose (26.6%), most of which were grade ≤2 (17.6%). Pancreatitis reductions associated with adverse reactions were reported was rare and reported in 1 of 295 patients; however, other in 21.7% and 19.7% of patients, respectively. potential confounding factors were noted with this patient. Hyperlipidemia is the most common adverse drug reaction Lipase elevations were often sporadic throughout the course of associated with lorlatinib and is largely manageable with lipid- treatment and episodic in some patients. Based on laboratory lowering therapy. In our analysis, most patients (81.0%) received data, increases in lipase generally occurred within 2 months of at least one lipid-lowering agent, and 22.1% and 30.8% required starting lorlatinib treatment (median time to onset, 62 days two or more agents for hypercholesterolemia and hypertrigly- [range, 7–619]). Distributions of lipase levels across treatment ceridemia, respectively. Therefore, patients should be informed cycles are shown in supplemental online Figure 7. that they may experience these adverse events and be moni- Dose interruptions and dose reductions due to lipase ele- tored throughout treatment. The CNS effects associated with vations were reported in nine (3.1%) and three (1.0%) patients, lorlatinib generally improved or resolved following dose modifi- respectively. General guidance on dose modifications should cations. Patients, and importantly patients’ family members be applied to grade ≥3 adverse events (Table 6). and/or caregivers, should be advised to alert health care pro- viders if any CNS-related symptoms arise. The proactive counsel- Gastrointestinal Effects ing of patients on how to manage adverse events, as well as Gastrointestinal side effects such as constipation and diarrhea pre-emptive monitoring and treatment, is an integral compo- occurred in 14.2% and 17.6% of patients treated with lorlati- nent of patient care when initiating lorlatinib or any new treat- nib 100 mg QD, respectively, and were predominantly mild in ment regimen. Other adverse drug reactions with lorlatinib are severity. No grade ≥3 constipation adverse events were primarilymildtomoderateinseverityand canalsobeeffectively reported, and only two patients (0.7%) experienced grade managed with dose modifications and/or standard supportive 3diarrhea. Dose modifications were rarely required, and no medical therapy. patients discontinued lorlatinib as a result of gastrointestinal adverse events. General guidance should be followed in more CONCLUSION severe cases (Table 6), and constipation and diarrhea can be Lorlatinib has a unique safety profile to be considered when pre- managed with standard medical therapy. scribed for the treatment of patients with ALK-positive, metastatic, www.TheOncologist.com © AlphaMed Press 2019 Downloaded from https://academic.oup.com/oncolo/article/24/8/1103/6439309 by DeepDyve user on 01 February 2022 1110 Management of Adverse Events with Lorlatinib Manuscript writing: Todd M. Bauer, Enriqueta Felip, Benjamin J. Solomon, advanced NSCLC previously treated with a second-generation Holger Thurm, Gerson Peltz, Marc D. Chioda, Alice T. Shaw ALK TKI. A phase III study comparing lorlatinib with crizotinib in Final approval of manuscript: Todd M. Bauer, Enriqueta Felip, Benjamin treatment-naïve, ALK-positive, advanced NSCLC is underway. J. Solomon, Holger Thurm, Gerson Peltz, Marc D. Chioda, Alice T. Shaw ACKNOWLEDGMENTS DISCLOSURES Medical writing support was provided by Jade Drummond and Todd M. Bauer: Guardant Health, Ignyta, Loxo, Moderna Therapeutics, Pfizer (C/A); Enriqueta Felip: Celgene, Eli Lilly, Brian Szente of inScience Communications, Springer Health- Guardant Health, Takeda, AstraZeneca, Boehringer Ingelheim, care (Chester, U.K., and Philadelphia, PA), and was funded by Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Pfizer, Pfizer Inc. We thank Leonard P. James, formerly of Pfizer Inc., Roche (C/A), AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Pfizer, Roche (H); for insightful discussion and review of the manuscript. Benjamin J. Solomon: AstraZeneca, Eisai (C/A), AstraZeneca, Bristol-Myers Squibb, Merck, Novartis, Roche (other: travel expenses), Biodesix (VeriStrat) (IP), AstraZeneca, Bristol-Myers AUTHOR CONTRIBUTIONS Squibb (H); Holger Thurm: Pfizer (E, OI); Gerson Peltz: Pfizer (E, Conception/design: Todd M. Bauer, Enriqueta Felip, Benjamin J. Solomon, OI); Marc D. Chioda: Pfizer (E, OI); Alice T. Shaw: Ariad, Blueprint Holger Thurm, Gerson Peltz, Marc D. Chioda, Alice T. Shaw Medicines, Daiichi Sankyo, EMD Serono, Genentech, Ignyta, KSQ Provision of study material or patients: Todd M. Bauer, Enriqueta Felip, Therapeutics, Natera, Novartis, Pfizer, Roche and Taiho Benjamin J. Solomon, Alice T. Shaw Pharmaceutical (C/A), Novartis, Pfizer, Roche/Genentech (RF), Collection and/or assembly of data: Todd M. Bauer, Enriqueta Felip, Benjamin Novartis, Pfizer, Roche/Genentech, Foundation Medicine (H). J. Solomon, Holger Thurm, Gerson Peltz, Marc D. Chioda, Alice T. Shaw (C/A) Consulting/advisory relationship; (RF) Research funding; (E) Employment; (ET) Expert Data analysis and interpretation: Todd M. Bauer, Enriqueta Felip, Benjamin testimony; (H) Honoraria received; (OI) Ownership interests; (IP) Intellectual property J. Solomon, Holger Thurm, Gerson Peltz, Marc D. Chioda, Alice T. Shaw rights/inventor/patent holder; (SAB) Scientific advisory board REFERENCES 1. Koivunen JP, Mermel C, Zejnullahu K et al. lung cancer: A single-group, multicentre, phase resistance to first and second generation ALK EML4-ALK fusion gene and efficacy of an ALK 2 trial. Lancet Oncol 2016;17:234–242. inhibitors in preclinical models. Cancer Cell 2015; kinase inhibitor in lung cancer. Clin Cancer Res 28:70–81. 11. Shaw AT, Kim DW, Mehra R et al. Ceritinib 2008;14:4275–4283. in ALK-rearranged non-small-cell lung cancer. N 19. Shaw AT, Felip E, Bauer TM et al. Lorlatinib 2. Kris MG, Johnson BE, Berry LD et al. Using Engl J Med 2014;370:1189–1197. in non-small-cell lung cancer with ALK or ROS1 multiplexed assays of oncogenic drivers in lung rearrangement: An international, multicentre, open- 12. Gainor JF, Dardaei L, Yoda S et al. Molecular cancers to select targeted drugs. JAMA 2014; label, single-arm first-in-man phase 1 trial. Lancet mechanisms of resistance to first- and second- 311:1998–2006. Oncol 2017;18:1590–1599. generation ALK inhibitors in ALK-rearranged lung 3. Takeuchi K, Choi YL, Soda M et al. Multiplex cancer. Cancer Discov 2016;6:1118–1133. 20. Solomon BJ, Shaw AT, Ou S-HI et al. Phase reverse transcription-PCR screening for EML4- 2 study of lorlatinib in patients with advanced 13. Novello S, Mazieres J, Oh IJ et al. Primary ALK fusion transcripts. Clin Cancer Res 2008;14: ALK+/ROS1+ non-small-cell lung cancer. Paper results from the phase III ALUR study of alectinib 6618–6624. presented at: International Association for the Study versus chemotherapy in previously treated ALK+ of Lung Cancer 18th World Conference on Lung Can- 4. Takeuchi K, Soda M, Togashi Y et al. RET, non-small-cell lung cancer (NSCLC). Ann Oncol cer; October 15–18, 2017; Yokohama, Japan. ROS1 and ALK fusions in lung cancer. Nat Med 2017;28(suppl 5):1299O_PRa. 2012;18:378–381. 21. Solomon BJ, Besse B, Bauer TM et al. Lorla- 14. Shaw AT, Kim DW, Nakagawa K et al. Crizoti- tinib in patients with ALK-positive non-small-cell 5. Solomon BJ, Mok T, Kim DW et al. First-line nib versus chemotherapy in advanced ALK-positive lung cancer: Results from a global phase 2 study. crizotinib versus chemotherapy in ALK-positive lung cancer. N Engl J Med 2013;368:2385–2394. Lancet Oncol 2018;19:1654–1667. lung cancer. N Engl J Med 2014;371:2167–2177. 15. Shaw AT, Kim TM, Crino L et al. Ceritinib 22. Neuvonen PJ, Niemi M, Backman JT. Drug 6. Kim DW, Tiseo M, Ahn MJ et al. Brigatinib in versus chemotherapy in patients with ALK- interactions with lipid-lowering drugs: Mecha- patients with crizotinib-refractory anaplastic lym- rearranged non-small-cell lung cancer previously nisms and clinical relevance. Clin Pharmacol Ther phoma kinase-positive non-small-cell lung can- given chemotherapy and crizotinib (ASCEND-5): A 2006;80:565–581. cer: A randomized, multicenter phase II trial. randomised, controlled, open-label, phase 3 trial. J Clin Oncol 2017;35:2490–2498. 23. Reiner Z, Catapano AL, De Backer G et al. Lancet Oncol 2017;18:874–886. ESC/EAS guidelines for the management of dysli- 7. Peters S, Camidge DR, Shaw AT et al. Alecti- 16. Johnson TW, Richardson PF, Bailey S et al. pidaemias: The task force for the management of nib versus crizotinib in untreated ALK-positive Discovery of (10R)-7-amino-12-fluoro-2,10,16-tri- dyslipidaemias of the European Society of Cardiol- non-small-cell lung cancer. N Engl J Med 2017; methyl-15-oxo-10,15,16,17-tetrahydro-2h-8,4-(m ogy (ESC) and the European Atherosclerosis Soci- 377:829–838. etheno)pyrazolo[4,3-h][2,5,11]-benzoxadiazacy- ety (EAS). Eur Heart J 2011;32:1769–1818. clotetradecine-3-carbonitrile (PF-06463922), a macrocyclic 8. Soria JC, Tan DSW, Chiari R, et al. First-line 24. Niaspan (niacin extended-release): U.S. pre- inhibitor of anaplastic lymphoma kinase (ALK) and ceritinib versus platinum-based chemotherapy in scribing information. North Chicago, IL: Abbvie Inc., c-ros oncogene 1 (ROS1) with preclinical brain advanced ALK-rearranged non-small-cell lung can- exposure and broad-spectrum potency against cer (ASCEND-4): A randomised, open-label, phase ALK-resistant mutations. J Med Chem 2014;57: 3 study. Lancet 2017;389:917–929. 25. Fenoglide (fenofibrate): U.S. prescribing infor- 4720–4744. mation. San Diego, CA: Santarus, Inc.; 2012. 9. Katayama R, Shaw AT, Khan TM et al. Mech- 17. Schinkel AH. P-glycoprotein, a gatekeeper anisms of acquired crizotinib resistance in ALK- 26. Lovaza (omega-3-acid ethyl esters): U.S. in the blood-brain barrier. Adv Drug Deliv Rev rearranged lung cancers. Sci Transl Med 2012;4: prescribing information. Research Triangle Park, 1999;36:179-194. 120ra117. NC: GlaxoSmithKline, 2015. 10. Shaw AT, Gandhi L, Gadgeel S et al. Alectinib 18. Zou HY, Friboulet L, Kodack DP et al. PF- 27. Lopid (gemfibrozil): Summary of product char- in ALK-positive, crizotinib-resistant, non-small-cell 06463922, an ALK/ROS1 inhibitor, overcomes acteristics. Kent, U.K.: Pfizer Ltd, 2016. See http://www.TheOncologist.com for supplemental material available online. © AlphaMed Press 2019

Journal

The OncologistOxford University Press

Published: Aug 1, 2019

There are no references for this article.