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LORBRENA is indicated for the treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) whose tumors are anaplastic lymphoma kinase (ALK)-positive as detected by an FDA-approved test.

Important Safety Information

Contraindications: LORBRENA is contraindicated in patients taking strong CYP3A inducers, due to the potential for serious hepatotoxicity.

Risk of Serious Hepatotoxicity with Concomitant Use of Strong CYP3A Inducers:
Severe hepatotoxicity occurred in 10 of 12 healthy subjects receiving a single dose of LORBRENA with multiple daily doses of rifampin, a strong CYP3A inducer. Grade 4 ALT or AST elevations occurred in 50% of subjects, Grade 3 in 33% of subjects, and Grade 2 in 8% of subjects. ALT or AST elevations occurred within 3 days and returned to within normal limits after a median of 15 days (7 to 34 days); median time to recovery in subjects with Grade 3 or 4 or Grade 2 ALT or AST elevations was 18 days and 7 days, respectively. LORBRENA is contraindicated in patients taking strong CYP3A inducers. Discontinue strong CYP3A inducers for 3 plasma half-lives of the strong CYP3A inducer prior to initiating LORBRENA.

Please scroll down for additional Important Safety Information.

Dear Healthcare Provider,

Review the PFS results from the primary and latest follow-up analyses for LORBRENA. See how the CROWN data may help inform your first-line treatment decision for your next patient with ALK+ mNSCLC.^1,2

Study design: CROWN is a global, open-label, randomized, multicenter, Phase 3 trial in which 296 adults with previously untreated ALK-positive locally advanced or metastatic NSCLC were randomized 1:1 to receive LORBRENA 100 mg QD (n=149) or crizotinib 250 mg BID (n=147). The major efficacy outcome measure of the trial is PFS based on BICR. Additional efficacy outcome measures included ORR, DoR, IC-ORR, IC-DoR, and OS.^1-3

In the primary analysis of the first-line ALK+ mNSCLC CROWN trial

Superior progression-free survival vs crizotinib^1,3

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mPFS was not reached for LORBRENA vs 9.3 months (95% CI: 7.6-11.1) for crizotinib at the 18.3-month follow-up (HR=0.28 [95% CI: 0.19-0.41]; P<0.0001)^1,3

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At the data cutoff, OS data were not mature¹

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ORR^† for LORBRENA was 76% (95% CI: 68-83) vs 58% (95% CI: 49-66) for crizotinib³

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Response duration ≥12 months for LORBRENA was 70% vs 27% for crizotinib¹

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For LORBRENA, 73% partial response and 3% complete response; for crizotinib, 58% partial response and 0% complete response³

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IC-ORR^†‡ for LORBRENA was 82% (95% CI: 57-96) vs 23% (95% CI: 5-54) for crizotinib^3,4§

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Response duration ≥12 months for LORBRENA was 79% vs 0% for crizotinib¹

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For LORBRENA, 12% partial response and 71% complete response; for crizotinib, 15% partial response and 8% complete response^3,4§

Based on 1-sided stratified log-rank test.¹

^†

Assessed by BICR per RECIST v1.1.^1,3

^‡

Intracranial response and DoR were evaluated in a prespecified exploratory analysis of 30 patients with measurable CNS lesions at baseline.¹

^§

Rounded values.⁴

In an exploratory analysis of the first-line ALK+ mNSCLC CROWN trial

Median progression-free survival was not reached at 83 months (95% CI: 68.5-NR)²

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Patients on LORBRENA had a 55% probability of being alive and progression free at 7 years²

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81% reduction in risk of progression or death vs crizotinib (investigator-assessed) (HR=0.19 [95% CI: 0.13-0.26])²

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At the data cutoff, OS data were not mature²

LORBRENA has an established safety profile²

Adverse reactions in the CROWN trial¹

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Serious adverse reactions occurred in 34% of the 149 patients treated with LORBRENA; the most frequently reported serious adverse reactions were pneumonia (4.7%), dyspnea (2.7%), respiratory failure (2.7%), cognitive effects (2.0%), and pyrexia (2.0%). Fatal adverse reactions occurred in 3.4% of patients and included pneumonia (0.7%), respiratory failure (0.7%), cardiac failure acute (0.7%), pulmonary embolism (0.7%), and sudden death (0.7%)

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The most frequently reported (≥20%) adverse reactions for LORBRENA and crizotinib, respectively, were edema (56% vs 40%; 4% vs 1.4% [Grade 3 or 4]), weight gain (38% vs 13%; 17% vs 2.1%); peripheral neuropathy (34% vs 15%; 2% vs 0.7%), cognitive effects (21% vs 6%; 2% vs 0%), diarrhea (21% vs 52%; 1.3% vs 0.7%), and dyspnea (20% vs 16%; 2.7% vs 2.1%)

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The most frequent laboratory abnormalities for LORBRENA and crizotinib, respectively, were hypertriglyceridemia (95% vs 27%; 22% vs 0% [Grade 3 or 4]), hypercholesterolemia (91% vs 12%; 19% vs 0%), increased creatinine (81% vs 99%; 0.7% vs 2.1%), increased GGT (52% vs 41%; 6% vs 6%), hyperglycemia (48% vs 27%; 7% vs 2.1%), anemia (48% vs 38%; 2% vs 2.8%), increased AST (48% vs 75%; 2% vs 3.5%), increased ALT (44% vs 75%; 2.7% vs 4.3%), increased CPK (39% vs 64%; 2% vs 5%), and hypoalbuminemia (36% vs 61%; 0.7% vs 6%)

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Median duration of exposure to LORBRENA was 16.7 months (range, 4 days to 34.3 months); 76% of patients received LORBRENA for at least 12 months

Therapy management strategies

Discussing ARs with patients and their care partners prior to and during treatment with LORBRENA is important for appropriate therapy management.⁵

When your patients experience ARs, there are ways to monitor, assess, and help manage ARs to support patients on LORBRENA.⁵

Explore more about therapy management strategies for specific adverse reactions, including dose modifications.¹

IMPORTANT SAFETY INFORMATION (CONT'D)

Central Nervous System (CNS) Effects: A broad spectrum of CNS effects can occur; overall, CNS effects occurred in 52% of the 476 patients receiving LORBRENA. These included seizures (1.9%, sometimes in conjunction with other neurologic findings), psychotic effects (7%; 0.6% severe [Grade 3 or 4]), and changes in cognitive function (28%; 2.9% severe), mood (including suicidal ideation) (21%; 1.7% severe), speech (11%; 0.6% severe), mental status (1.3%; 1.1% severe), and sleep (12%). Median time to first onset of any CNS effect was 1.4 months (1 day to 3.4 years). Overall, 2.1% and 10% of patients required permanent or temporary discontinuation of LORBRENA, respectively, for a CNS effect; 8% required dose reduction. Withhold and resume at same or reduced dose or permanently discontinue based on severity.

Hyperlipidemia: Increases in serum cholesterol and triglycerides can occur. Grade 3 or 4 elevations in total cholesterol occurred in 18% and Grade 3 or 4 elevations in triglycerides occurred in 19% of the 476 patients who received LORBRENA. Median time to onset was 15 days for both hypercholesterolemia and hypertriglyceridemia. Approximately 4% and 7% of patients required temporary discontinuation and 1% and 3% of patients required dose reduction of LORBRENA for elevations in cholesterol and in triglycerides in Study B7461001 and Study B7461006, respectively. Eighty-three percent of patients required initiation of lipid-lowering medications, with a median time to onset of start of such medications of 17 days. Initiate or increase the dose of lipid-lowering agents in patients with hyperlipidemia. Monitor serum cholesterol and triglycerides before initiating LORBRENA, 1 and 2 months after initiating LORBRENA, and periodically thereafter. Withhold and resume at same dose for the first occurrence; resume at same or reduced dose of LORBRENA for recurrence based on severity.

Atrioventricular (AV) Block: PR interval prolongation and AV block can occur. In 476 patients who received LORBRENA at a dose of 100 mg orally once daily and who had a baseline electrocardiography (ECG), 1.9% experienced AV block and 0.2% experienced Grade 3 AV block and underwent pacemaker placement. Monitor ECG prior to initiating LORBRENA and periodically thereafter. Withhold and resume at reduced or same dose in patients who undergo pacemaker placement. Permanently discontinue for recurrence in patients without a pacemaker.

Interstitial Lung Disease (ILD)/Pneumonitis: Severe or life-threatening pulmonary adverse reactions consistent with ILD/pneumonitis can occur. ILD/pneumonitis occurred in 1.9% of patients, including Grade 3 or 4 ILD/pneumonitis in 0.6% of patients. Four patients (0.8%) discontinued LORBRENA for ILD/pneumonitis. Promptly investigate for ILD/pneumonitis in any patient who presents with worsening of respiratory symptoms indicative of ILD/pneumonitis (e.g., dyspnea, cough, and fever). Immediately withhold LORBRENA in patients with suspected ILD/pneumonitis. Permanently discontinue LORBRENA for treatment-related ILD/pneumonitis of any severity.

Hypertension: Hypertension can occur. Hypertension occurred in 13% of patients, including Grade 3 or 4 in 6% of patients. Median time to onset of hypertension was 6.4 months (1 day to 2.8 years), and 2.3% of patients temporarily discontinued LORBRENA for hypertension. Control blood pressure prior to initiating LORBRENA. Monitor blood pressure after 2 weeks and at least monthly thereafter. Withhold and resume at reduced dose or permanently discontinue based on severity.

Hyperglycemia: Hyperglycemia can occur. Hyperglycemia occurred in 9% of patients, including Grade 3 or 4 in 3.2% of patients. Median time to onset of hyperglycemia was 4.8 months (1 day to 2.9 years), and 0.8% of patients temporarily discontinued LORBRENA for hyperglycemia. Assess fasting serum glucose prior to initiating LORBRENA and monitor periodically thereafter. Withhold and resume at reduced dose or permanently discontinue based on severity.

Embryo-fetal Toxicity: LORBRENA can cause fetal harm. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use an effective non-hormonal method of contraception, since LORBRENA can render hormonal contraceptives ineffective, during treatment with LORBRENA and for at least 6 months after the final dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with LORBRENA and for 3 months after the final dose.

Adverse Reactions: In the pooled safety population of 476 patients who received 100 mg LORBRENA once daily, the most frequent (≥ 20%) adverse reactions were edema (56%), peripheral neuropathy (44%), weight gain (31%), cognitive effects (28%), fatigue (27%), dyspnea (27%), arthralgia (24%), diarrhea (23%), mood effects (21%), and cough (21%). The most frequent (≥ 20%) Grade 3-4 laboratory abnormalities in patients receiving LORBRENA were hypercholesterolemia (21%) and hypertriglyceridemia (21%).

In previously untreated patients, serious adverse reactions occurred in 34% of the 149 patients treated with LORBRENA; the most frequently reported serious adverse reactions were pneumonia (4.7%), dyspnea (2.7%), respiratory failure (2.7%), cognitive effects (2.0%), and pyrexia (2.0%). Fatal adverse reactions occurred in 3.4% of patients and included pneumonia (0.7%), respiratory failure (0.7%), cardiac failure acute (0.7%), pulmonary embolism (0.7%), and sudden death (0.7%). In the Phase 1/2 study, serious adverse reactions occurred in 32% of the 295 patients; the most frequently reported serious adverse reactions were pneumonia (3.4%), dyspnea (2.7%), pyrexia (2%), mental status changes (1.4%), and respiratory failure (1.4%). Fatal adverse reactions occurred in 2.7% of patients and included pneumonia (0.7%), myocardial infarction (0.7%), acute pulmonary edema (0.3%), embolism (0.3%), peripheral artery occlusion (0.3%), and respiratory distress (0.3%).

Drug Interactions: LORBRENA is contraindicated in patients taking strong CYP3A inducers. Avoid concomitant use with moderate CYP3A inducers, strong CYP3A inhibitors, and fluconazole. If concomitant use of moderate CYP3A inducers cannot be avoided, increase the LORBRENA dose as recommended. If concomitant use with a strong CYP3A inhibitor or fluconazole cannot be avoided, reduce the LORBRENA dose as recommended. Avoid concomitant use of LORBRENA with CYP3A substrates and P-gp substrates, which may reduce the efficacy of these substrates.

Lactation: Because of the potential for serious adverse reactions in breastfed infants, instruct women not to breastfeed during treatment with LORBRENA and for 7 days after the final dose.

Hepatic Impairment: No dose adjustment is recommended for patients with mild (total bilirubin ≤ ULN with AST > ULN or total bilirubin >1 to 1.5 × ULN with any AST) to moderate (Child-Pugh B) hepatic impairment. In patients with severe hepatic impairment (Child-Pugh C), the recommended dosage of LORBRENA is 50 mg orally once daily.

Renal Impairment: In patients with CLcr 15 to <30 mL/min (estimated by Cockcroft-Gault), the recommended dosage of LORBRENA is 75 mg orally once daily. No dose adjustment is recommended for patients with CLcr 30 to 89 mL/min (estimated by Cockcroft-Gault).

INDICATION

LORBRENA is indicated for the treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) whose tumors are anaplastic lymphoma kinase (ALK)-positive as detected by an FDA-approved test.

Please see full Prescribing Information for LORBRENA.

Information on FDA-approved tests for the detection of ALK rearrangements in NSCLC is available at http://www.fda.gov/CompanionDiagnostics.

ALK=anaplastic lymphoma kinase; ALK+=anaplastic lymphoma kinase–positive; ALT=alanine aminotransferase; AR=adverse reaction; AST=aspartate aminotransferase; BICR=Blinded Independent Central Review; BID=twice daily; CI=confidence interval; CNS=central nervous system; CPK=creatine phosphokinase; DoR=duration of response; FDA=US Food and Drug Administration; GGT=gamma-glutamyl transferase; HR=hazard ratio; IC-DoR=intracranial duration of response; IC-ORR=intracranial overall response rate; mNSCLC=metastatic non–small cell lung cancer; mPFS=median progression-free survival; NE=not estimable; NR=not reached; NSCLC=non–small cell lung cancer; ORR=overall response rate; OS=overall survival; PFS=progression-free survival; QD=once daily; RECIST=Response Evaluation Criteria in Solid Tumors.

References:

LORBRENA^® (lorlatinib) Prescribing Information. Pfizer Inc; January 2026.

Shaw AT, Solomon BJ, Felip E, et al. Lorlatinib versus crizotinib as first-line treatment for advanced ALK-positive non-small cell lung cancer: 7-year update from the phase 3 CROWN study. Ann Oncol. 2026; doi: https://doi.org/10.1016/j.annonc.2026.05.692

Shaw AT, Bauer TM, de Marinis F, et al; CROWN Trial Investigators. First-line lorlatinib or crizotinib in advanced ALK-positive lung cancer. N Engl J Med. 2020;383(21):2018-2029.

Data on file. Pfizer Inc, New York, NY.

Liu G, Mazieres J, Stratmann J, et al. A pragmatic guide for management of adverse events associated with lorlatinib. Lung Cancer. 2024;191:107535.

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