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Lorlatinib in Second- or Third-Line Treatment of ALK-Positive Metastatic Non–Small Cell Lung Cancer


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On November 2, 2018, lorlatinib (Lorbrena) was granted accelerated approval for the treatment of patients with ALK-positive metastatic non–small cell lung cancer (NSCLC) whose disease has progressed on crizotinib (Xalkori) and at least one other ALK inhibitor for metastatic disease or whose disease has progressed on alectinib (Alecensa) or ceritinib (Zykadia) as the first ALK inhibitor therapy for metastatic disease.1,2

Supporting Efficacy Data

The approval was based on overall response rate, intracranial overall response rate, and duration of response with lorlatinib treatment in a subgroup of 215 patients in a phase II trial (Study B7461001; ClinicalTrials.gov identifier NCT01970865) who had ALK-positive metastatic NSCLC previously treated with 1 or more ALK kinase inhibitors.2,3 Patients received oral lorlatinib at 100 mg once daily.

OF NOTE

Lorlatinib carries warnings and precautions for the risk of serious hepatotoxicity with concomitant use of strong CYP3A inducers, CNS effects, hyperlipidemia, atrioventricular block, interstitial lung disease or pneumonitis, and embryofetal toxicity.

Patients had a median age of 53 years (18% aged ≥ 65 years), 59% were female, 51% were white and 34% were Asian, Eastern Cooperative Oncology Group performance status was 0 or 1 in 96%, 95% had adenocarcinoma, and 69% had brain metastases identified by independent central review; of them, 60% had received prior radiotherapy to the brain and 60% (n = 89) had measurable central nervous system (CNS) disease per independent central review.

The overall response rate was 48%, with a complete response in 4% of patients. The estimated median duration of response was 12.5 months. The intracranial overall response rate in 89 patients with measurable CNS lesions was 60%, with a complete response in 21%. The estimated median duration of intracranial response was 19.5 months. Exploratory analyses showed overall response rates of 39% among 119 patients who had received crizotinib and at least one other ALK inhibitor, 31% among 13 patients who had received alectinib as the only ALK inhibitor, and 46% among 13 patients who received ceritinib as the only ALK inhibitor, all with or without prior chemotherapy.

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. It has shown in vitro activity against multiple mutant forms of the ALK enzyme, including some mutations detected in tumors at the time of disease progression on crizotinib and other ALK inhibitors.

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

The recommended dose of lorlatinib is 100 mg once daily until disease progression or unacceptable toxicity. Dose reduction for adverse reactions are stepwise to 75 mg once daily and then 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 for grade 1, grade 2 or 3, and grade 4 CNS adverse reactions; grade 4 hypercholesterolemia or 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 or pneumonitis; and other grade 1 or 2 and grade 3 or 4 adverse reactions. Lorlatinib treatment should be permanently discontinued for grade 4 CNS adverse reactions, recurrent complete atrioventricular block if a pacemaker is not placed, and any-grade treatment-related interstitial lung disease or pneumonitis.

LORLATINIB IN METASTATIC NSCLC

  • Lorlatinib (Lorbrena) was approved to treat ALK-positive metastatic non–small cell lung cancer (NSCLC) that has progressed on crizotinib and at least one other ALK inhibitor for metastatic disease or that has progressed on alectinib or ceritinib as the first ALK inhibitor for metastatic disease.
  • The recommended dose of lorlatinib is 100 mg once daily until disease progression or unacceptable toxicity.

Lorlatinib is contraindicated in patients taking strong CYP3A inducers (eg, phenytoin, rifampin, carbamazepine, St. John’s wort), as severe hepatotoxicity occurred in 10 of 12 healthy subjects receiving a single dose of lorlatinib with multiple daily doses of the strong CYP3A inducer rifampin. Strong CYP3A inducers should be discontinued for three plasma half-lives of the strong inducer prior to initiating lorlatinib treatment. Concomitant use with moderate CYP3A inducers should be avoided.

Concomitant use with strong CYP3A inhibitors (eg, ketoconazole, conivaptan, clarithromycin, indinavir, itraconazole) should be avoided; if their use cannot be avoided, the dose of lorlatinib should be reduced from 100 mg to 75 mg once daily or to 50 mg once daily if the dose has already been reduced to 75 mg once daily due to an adverse reaction. If the strong CYP3A inhibitor is discontinued, lorlatinib can be resumed (after three plasma half-lives of the strong CYP3A inhibitor) at the dose used prior to starting the strong inhibitor. Concomitant use with CYP3A substrates (eg, aprepitant, budesonide, lovastatin, midazolam) should be avoided where minimal concentration changes of the substrates may lead to serious therapeutic failures. Lorlatinib decreases concentrations of CYP3A substrates.

Safety Profile

The most common adverse events (≥ 20%) of any grade occurring in the total population of 295 patients receiving lorlatinib in the phase II trial were edema (57%), peripheral neuropathy (47%), cognitive effects (27%), dyspnea (27%), fatigue (26%), weight gain (24%), arthralgia (23%), mood effects (23%), and diarrhea (22%). The most common grade 3 or 4 adverse events included dyspnea (5.4%), weight gain (4.4%), and edema (3.1%).

The most common grade 3 or 4 laboratory abnormalities included hypercholesterolemia (18%), hypertriglyceridemia (18%), and hyperglycemia (5%). Serious adverse events occurred in 32% of patients, with the most common being pneumonia (3.4%), dyspnea (2.7%), pyrexia (2%), mental status changes (1.4%), and respiratory failure (1.4%), and adverse events led to dose interruption in 48%. Adverse events led to permanent discontinuation of treatment in 8%, and fatal adverse events occurred in 2.7% of patients.

Lorlatinib carries warnings and precautions for the risk of serious hepatotoxicity with concomitant use of strong CYP3A inducers; CNS effects, including seizures, hallucinations and changes in cognitive function, mood (including suicidal ideation), speech, mental status, and sleep; hyperlipidemia; atrioventricular block; interstitial lung disease or pneumonitis; and embryofetal toxicity. Patients should be advised not to breastfeed during lorlatinib therapy. 

REFERENCES

1. U.S. Food and Drug Administration: FDA approves lorlatinib for second- or third-line treatment of ALK-positive metastatic NSCLC. Available at www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm625027.htm. Accessed November 19, 2018.

2. Lorbrena (lorlatinib) tablets prescribing information, Pfizer Inc, November 2018. Available at www.accessdata.fda.gov/drugsatfda_docs/label/2018/210868s000lbl.pdf. Accessed November 19, 2018.

3. 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 19:1654-1667, 2018.


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