November 2, 2018, with PAP

On November 2, 2018, the Food and Drug Administration granted accelerated approval to lorlatinib (LORBRENA, Pfizer, Inc.) for patients with anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC) whose disease has progressed on crizotinib and at least one other ALK inhibitor for metastatic disease or whose disease has progressed on alectinib or ceritinib as the first ALK inhibitor therapy for metastatic disease.

Approval was based on a subgroup of 215 patients with ALK-positive metastatic NSCLC, previously treated with one or more ALK kinase inhibitors, enrolled in a non‑randomized, dose-ranging and activity-estimating, multi‑cohort, multicenter study (Study B7461001; NCT01970865). The major efficacy measures were overall response rate (ORR) and intracranial ORR, according to RECIST 1.1, as assessed by an independent central review committee.

The ORR was 48% (95% CI: 42, 55), with 4% complete and 44% partial responses. The estimated median response duration was 12.5 months (95% CI: 8.4, 23.7). The intracranial ORR in 89 patients with measurable lesions in the CNS according to RECIST 1.1 was 60% (95% CI: 49, 70) with 21% complete and 38% partial responses. The estimated median response duration was 19.5 months (95% CI: 12.4, not reached).

Most common adverse reactions (incidence ≥20%) in patients receiving lorlatinib were edema, peripheral neuropathy, cognitive effects, dyspnea, fatigue, weight gain, arthralgia, mood effects, and diarrhea. The most common laboratory abnormalities were hypercholesterolemia and hypertriglyceridemia.

The FL indication is based on a single-arm multicenter trial of duvelisib (NCT02204982) enrolling 83 patients with FL who were refractory to rituximab and to either chemotherapy or radioimmunotherapy. The ORR, determined by an IRC, was 42% (95% CI: 31, 54), with 41% of patients experiencing partial responses and one patient having a complete response. Of the 35 responding patients,15 (43%) maintained responses for at least 6 months and 6 (17%) maintained responses for at least 12 months. Continued approval for the FL indication may be contingent upon verification of clinical benefit demonstrated in a planned randomized trial.

The recommended lorlatinib dose is 100 mg orally once daily.

View full prescribing information for LORBRENA.

This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial. FDA granted this application priority review and granted breakthrough therapy designation for this development program. FDA expedited programs are described in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics.

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System by completing a form online at, by faxing (1-800-FDA-0178) or mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).

Pharmacist’s Applications to Practice

Lorlatinib for the Treatment of ALK-Positive Metastatic Non-Small-Cell Lung Cancer

Author: Tiba Al Sagheer, PharmD
PGY2 Oncology Pharmacy Resident
Skaggs School of Pharmacy and Pharmaceutical Sciences
University of Colorado–Anschutz Campus
Aurora, CO

What is the potential role for lorlatinib in the management of ALK-positive metastatic non-small-cell lung cancer?1-7

  • Lorbrena (lorlatinib) is a third-generation tyrosine kinase inhibitor that targets anaplastic lymphoma kinase (ALK) and ROS proto-oncogene 1 (ROS1) tyrosine kinases. It has good central nervous system (CNS) penetration and inhibits a broad range of ALK resistance mutations that develop after treatment with first- and second-generation ALK inhibitors.
  • The only first-generation ALK inhibitor is Xalkori (crizotinib); second-generation ALK inhibitors include Alecensa (alectinib), Alunbrig (brigatinib), and Zykadia (ceritinib).
  • Lorlatinib was granted accelerated approval by the U.S. Food and Drug Administration (FDA) on November 2, 2018. It was approved for patients with ALK-positive metastatic non-small-cell lung cancer (NSCLC) who have progressed on first-line crizotinib plus at least one other ALK inhibitor and for patients whose disease progressed on first-line alectinib or ceritinib therapy.
    • FDA approval was given on the basis of data from a subgroup of patients (N = 215) with ALK-positive metastatic NSCLC who had been previously treated with one or more ALK inhibitors and had been enrolled in a nonrandomized dose-ranging (10–200 mg once daily or 35–100 mg twice daily) and activity-estimating multicohort multicenter phase 1 study (NCT01970865). Lorlatinib was in general well tolerated and exhibited both systemic and intracranial antitumor activity.
    • A subsequent phase 2 study enrolled patients into six expansion groups (EXP1–6) separated according to ALK or ROS1 status and prior therapy. All patients in the six groups received lorlatinib 100 mg once daily continuously in 21-day cycles until the disease progressed or an unacceptable level of toxicity was reached.
      • The primary endpoints were overall and intracranial tumor response, according to Response Evaluation Criteria in Solid Tumors version 1.1, as assessed by an independent central review committee.
      • The secondary endpoints were duration of response, intracranial duration of response, time to first tumor response, progression-free survival, safety and tolerability, assessment of mood, suicidal ideation and behavior, and cognitive function.
      • Patients with ALK-positive metastatic NSCLC were enrolled in cohort 1 (EXP1; n = 30) who were treatment naive; patients enrolled in cohorts 2–5 (EXP2–5) had received at least one previous ALK tyrosine kinase inhibitor. ROS1-positive patients (n = 47) were enrolled in cohort 6 (EXP6).
      • Of the patients in EXP1, 27 (90%; 95% confidence interval [CI], 73.5–97.9) had an objective response, with 26 achieving a partial response and 1 achieving a complete response. Three patients in EXP1 had measurable CNS disease at baseline; of those, two achieved a partial response (66.7%; 95% CI, 9.4–99.2).
      • A total of 198 patients were enrolled in EXP2–5; objective responses were observed in 93 patients (47%; 95% CI, 39.9–54.2), with 4 complete responses and 89 partial responses. Measurable CNS disease at baseline was present in 81 patients; of those, intracranial responses were observed in 51 patients (63%; 95% CI, 51.5–73.4).
        • Response rates by the type of second-generation ALK tyrosine kinase inhibitor the patient received before lorlatinib were comparable at approximately 37%–40%.
        • Both median time to overall first tumor response and median time to first intracranial response were 1.4 months (interquartile range 1.3–2.7), and the median progression-free survival was 7.3 months (95% CI, 5.6–11).
  • The National Comprehensive Cancer Network (NCCN) guidelines have been updated to reflect the recent FDA approval. Lorlatinib is added as a treatment option after disease progression on crizotinib and alectinib, brigatinib, or ceritinib and is also an option after disease progression on alectinib, brigatinib, or ceritinib (Category 2A recommendation). In addition, lorlatinib is recommended as a subsequent therapy option for select patients with ROS1-positive NSCLC whose disease has progressed after treatment with crizotinib or ceritinib (Category 2A recommendation).
  • Lorlatinib is currently the only FDA-approved ALK inhibitor for ALK-positive metastatic NSCLC after disease progression on alectinib and ceritinib. At this time limited studies show benefit in this setting. A recent retrospective analysis was conducted to evaluate the use of brigatinib in alectinib-refractory ALK-positive NSCLC; it showed a limited clinical activity of brigatinib in this setting.

What role can the pharmacist play in the management of patients on lorlatinib?1,8,9

  • Lorlatinib’s dosing for both ALK- and ROS1-positive metastatic NSCLC is 100 mg orally once daily, until disease progression or an unacceptable level of toxicity.
  • Lorlatinib is a major substrate of cytochrome P450 (CYP3A); therefore dose adjustments are necessary when it is used concomitantly with medications that affect CYP3A activity.
    • It is recommended that concomitant use of lorlatinib with strong CYP3A inhibitors be avoided. If concomitant use cannot be avoided, a dose reduction from 100 mg orally once daily to 75 mg orally once daily is necessary.
      • If concomitant use of a strong CYP3A inhibitor is discontinued, it is recommended that the initial lorlatinib dose be resumed after 3 plasma half-lives of the strong CYP3A inhibitor have passed.
      • In patients who have had a dose reduction to 75 mg orally once daily because of adverse reactions and who initiate treatment with a strong CYP3A inhibitor, further reduce the dose to 50 mg orally once daily.
    • Lorlatinib is contraindicated in patients taking strong CYP3A inducers because of the potential for serious hepatotoxicity. Discontinue strong CYP3A inducers for 3 plasma half-lives prior to initiating lorlatinib.
    • Avoid concomitant use of lorlatinib with moderate CYP3A inducers. If concomitant use cannot be avoided, monitor transaminases and bilirubin after 48 hours after the first dose and at least 3 times during the first week after initiation.
      • Severe hepatotoxicity occurred in 10 of 12 healthy subjects receiving a single dose of lorlatinib with multiple daily doses of rifampin. Transaminase elevations occurred within 3 days and returned to within normal limits after a median of 15 days (7–34 days).
  • Lorlatinib is a moderate CYP3A inhibitor. It is recommended that concomitant use of lorlatinib and CYP3A substrates with a narrow therapeutic window be avoided. If concomitant use cannot be avoided, close monitoring and dose modification of the substrate is recommended in accordance with the product labeling.
  • Lorlatinib may require dosage modifications for adverse reactions. The first dose reduction is to 75 mg orally once daily, and the second dose reduction is to 50 mg orally once daily. If patients are unable to tolerate the 50-mg daily dose, it is recommended that lorlatinib be permanently discontinued.
  • Lorlatinib does not require dose adjustment in patients with mild hepatic impairment or mild to moderate renal impairment. However, a dose was not established in patients with moderate or severe hepatic impairment or severe renal impairment.
  • For each patient receiving lorlatinib, pharmacists must check for appropriate usage and dosing during order verification, dispensing, and follow-up according to reported adverse reactions and concomitant medications.
    • Lorlatinib tablets must be swallowed whole and should not be chewed, crushed, or split. If the tablet’s integrity is compromised, patients should not ingest it.
    • Lorlatinib should be taken at the same time each day with or without food. If a dose is missed, the missed dose can be taken unless the next dose is due within 4 hours.
    • The most common treatment-related adverse events of any grade were hypercholesterolemia (81%), hypertriglyceridemia (60%), edema (43%), peripheral neuropathy (30%), cognitive effects (18%), and weight increase (18%). The most common grade 3–4 treatment-related adverse events were hypertriglyceridemia (16%) and hypercholesterolemia (15%). The most frequent serious treatment-related adverse event was cognitive effects, which occurred in 1% of patients. Adverse events may require pharmacologic management, during which pharmacists can provide guidance and recommendations.
    • It is recommended that ECGs be monitored prior to initiation and periodically during therapy because atrioventricular block can occur with the use of lorlatinib.
    • Severe or life-threatening interstitial lung disease and pneumonitis were reported in approximately 1% of patients. It is important to monitor the patients and educate them about the signs and symptoms of both.
  • The Pfizer Oncology Together assistance program can provide help for patients regarding medication acquisition. Financial assistance options are available for commercially insured, government insured, and uninsured patients. Patients may qualify for a co-pay card, free medication, or support from independent charitable foundations, or they may obtain extra help through Medicare Part D. For further information call 1.877.744.5675 or visit

Clinical Pearls1,8,10

  • Lorlatinib was studied in patients with ALK or ROS1 rearrangements, and therefore it is best to use this medication in patients who have these gene rearrangements.
  • Lorlatinib is supplied in 25-mg and 100-mg tablets. In practice, it is ideal to minimize the pill burden for patients and use the 100-mg tablets. However, in the instance that a patient may need to have a dose reduction because of interacting medications or toxicity, it may not be feasible to obtain the 25-mg tablets in a timely manner because of issues with medication supply and coverage. Therefore, it is crucial to discuss this situation with the provider as well as the patient early in the treatment in order to devise a plan.
  • Use caution when initiating lipid-lowering medications because of their metabolism by CYP3A. Agents that are not major substrates of CYP3A include pravastatin, fluvastatin, and rosuvastatin; pitavastatin is not metabolized by CYP3A.


  1. Lorbrena (lorlatinib) [package insert]. Mission, KS: Pfizer Inc.; 2018.
  2. U. S. Food and Drug Administration. FDA approves lorlatinib for second- or third-line treatment of ALK-positive metastatic NSCLC. Available at Accessed February 5, 2019.
  3. Qiao H, Lovly CM. Cracking the code of resistance across multiple lines of ALK inhibitor therapy in lung cancer. Cancer Discov. 2016;6(10):1084-1086.
  4. National Comprehensive Cancer Network. Non-Small Cell Lung Cancer (Version 3.2019). Available at Accessed February 5, 2019.
  5. Shaw AT, Felip E, Bauer TM, et al. Lorlatinib in non-small-cell lung cancer with ALK or ROS1 rearrangement: an international, multicentre, open-label, single-arm first-in-man phase 1 trial. Lancet Oncol. 2017;18(12):1590-1599.
  6. Solomon BJ, Besse B, Bauer TM, et al. Lorlatinib in patients with ALK-positive non-small-cell lung cancer: results from a global phase 2 study. Lancet Oncol. 2018;19(12):1654-1667.
  7. Lin JJ, Zhu VW, Schoenfeld AJ, et al. Brigatinib in patients with alectinib-refractory ALK-positive NSCLC. J Thorac Oncol. 2018;13(10):1530-1538.
  8. Rowan CG, Brunelli SM, Munson J, et al. Clinical importance of the drug interaction between statins and CYP3A4 inhibitors: a retrospective cohort study in The Health Improvement Network. Pharmacoepidemiol Drug Saf. 2012;21(5):494–506.
  9. Pfizer Oncology Together. Available at Accessed February 5, 2019.
  10. Livalo (pitavastatin) [package insert]. Cincinnati, OH: Patheon, Inc.; 2011.