On March 3, 2021, lorlatinib was granted regular approval for treatment of patients with metastatic non–small cell lung cancer (NSCLC) with ALK-positive tumors as detected by a U.S. Food and Drug Administration (FDA)-approved test.^1,2 The FDA simultaneously approved the Ventana ALK (D5F3) CDx Assay as a companion diagnostic for lorlatinib.

Lorlatinib received accelerated approval in November 2018 for the second- or third-line treatment of ALK-positive metastatic NSCLC.

Supporting Efficacy Data

Approval was based on findings in the open-label, phase III CROWN trial (Study B7461006; ClinicalTrials.gov identifier NCT03052608).^2,3 In the trial, 296 patients with no prior systemic therapy for metastatic disease were randomly assigned to receive lorlatinib at 100 mg orally once daily (n = 149) or crizotinib at 250 mg orally twice daily (n = 147), with treatment continued until disease progression or unacceptable toxicity.

Patients were required to have ALK-positive tumors detected by the Ventana ALK (D5F3) CDx assay. Neurologically stable patients with treated or untreated asymptomatic central nervous system (CNS) metastases were eligible for the trial. Patients with severe acute or chronic psychiatric conditions were excluded. The major efficacy outcome measure was progression-free survival as determined by blinded independent central review.

Median progression-free survival was not reached (95% confidence interval [CI] = not estimable to not estimable) in the lorlatinib group vs 9.3 months (95% CI = 7.6–11.1 months) in the crizotinib group (hazard ratio [HR] = 0.28, 95% CI = 0.19–0.41, P < .0001).

Overall survival data were immature at the time of the progression-free survival analysis. An objective response was observed in 76% vs 58% of patients, with a complete response in 3% vs 0%. The median duration of response was not estimable (range = 0.9–31.3 months) vs 11 months (range = 1.1–27.5 months), with responses persisting for at least 12 months in 70% vs 27% of responders.

Among the 17 patients in the lorlatinib group and 13 in the crizotinib group with measurable CNS lesions, an objective response on blinded independent central review was observed in 82% vs 23%, with a complete response in 71% vs 8%. The response was maintained for at least 12 months in 79% vs 0% of responders.

How It Works

Lorlatinib is a kinase inhibitor with in vitro activity against ALK and ROS1, as well as TYK1, FER, FPS, TRKA, TRKB, TRKC, FAK, FAK2, and ACK. Lorlatinib has shown in vitro activity against multiple mutant forms of the ALK enzyme.

Lorlatinib produced antitumor activity in mice with subcutaneously implanted tumors harboring EML4 fusions with either ALK variant 1 or ALK mutations. Lorlatinib also demonstrated antitumor activity and prolonged survival in mice with intracranially implanted EML4-ALK–driven tumor cell lines. The overall antitumor activity of lorlatinib in in vivo models was dose dependent and correlated with inhibition of ALK phosphorylation.

How It Is Used

Patients must be selected for treatment of metastatic NSCLC based on the presence of ALK positivity in tumor specimens as detected by an FDA-approved test.

The recommended dose of lorlatinib is 100 mg once daily until disease progression or unacceptable toxicity. Dose reductions for adverse reactions are stepwise to 75 mg once daily and to 50 mg once daily. Treatment should be permanently discontinued in patients who are unable to tolerate 50 mg once daily.

Lorlatinib prescribing information provides detailed information on dose modification, including dose reduction and withholding and discontinuing treatment for adverse reactions, including grade 1 to 4 CNS adverse reactions; grade 4 hypercholesterolemia and grade 4 hypertriglyceridemia second-degree atrioventricular block, first occurrence of complete atrioventricular block, and recurrent complete atrioventricular block; any-grade treatment-related interstitial lung disease/pneumonitis; grade 3 to 4 hypertension; grade 3 to 4 hyperglycemia; and other grade 1 to 2 or grade 3 to 4 adverse reactions.

Prescribing information provides instructions on treatment modifications necessary to avoid adverse drug-drug interactions. Concomitant use of lorlatinib with strong CYP3A inducers (eg, phenobarbital, rifampicin) is contraindicated. Concomitant use with moderate CYP3A inducers, strong CYP3A inhibitors, and fluconazole should be avoided. Concomitant use with certain CYP3A substrates (eg, everolimus, midazolam) should be avoided where minimal concentration changes of the substrates may lead to serious therapeutic failures. Concomitant use with certain P-glycoprotein substrates (eg, cyclosporin, digoxin) should be avoided where minimal concentration changes of the substrates may lead to serious therapeutic failures.

Safety Profile

In the CROWN trial, the median duration of exposure to lorlatinib was 16.7 months (range = 4 days to 34.3 months), with 76% of patients receiving treatment for at least 12 months.

The most common adverse events of any grade (≥ 20%) in the lorlatinib group were edema, peripheral neuropathy, cognitive effects, dyspnea, fatigue, weight gain, arthralgia, diarrhea, and mood effects. The most common grade 3 to 4 adverse events included dyspnea, weight gain, and edema. The most common grade 3 or 4 laboratory abnormalities were hypercholesterolemia, hypertriglyceridemia, and increased lipase.

Serious adverse events occurred in 34% of patients, the most common being pneumonia, dyspnea, respiratory failure, cognitive effects, and pyrexia. Adverse events led to dose interruption in 49% of patients. Treatment was permanently discontinued due to adverse events in 6.7% of patients. Adverse events led to death in 3.4% of patients.

Lorlatinib has warnings and precautions for risk of serious hepatotoxicity with concomitant use of strong CYP3A inducers; CNS effects; hyperlipidemia; atrioventricular block; interstitial lung disease/pneumonitis; hypertension; hyperglycemia; and embryofetal toxicity. Blood pressure should be monitored after 2 weeks and then at least monthly during treatment. Fasting serum glucose should be assessed prior to starting treatment and regularly during treatment. Treatment should be permanently discontinued for treatment-related interstitial lung disease/pneumonitis of any grade. Patients should be advised not to breastfeed while receiving lorlatinib. Concomitant use of lorlatinib and strong CYP3A inducers is contraindicated. 

REFERENCES

1. U.S. Food and Drug Administration: FDA approves lorlatinib for metastatic ALK-positive NSCLC. Available at https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-lorlatinib-metastatic-alk-positive-nsclc. Accessed April 7, 2021.

2. Lorbrena (lorlatinib) tablets prescribing information, Pfizer Inc, March 2021. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/210868s004lbl.pdf. Accessed April 7, 2021.

3. Shaw AT, Bauer TM, de Marinis F, et al: First-line lorlatinib or crizotinib in advanced ALK-positive lung cancer. N Engl J Med 383:2018-2029, 2020.