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First-Line

Prior ALK TKI

ALK+ mNSCLC Considerations

Tab Number 4

Tab Number 5

First-Line Efficacy: Primary and Follow-up AnalysesStudy Design LORBRENA in First-Line Treatment LORBRENA is a third-generation ALK inhibitor that was evaluated in a global, open-label, randomized, multicenter, Phase 3 trial1-3*

The demographic characteristics of the overall study population were: median age 59 years (range: 26 to 90 years), age ≥65 years (35%), 59% female, 49% White, 44% Asian, and 0.3% Black. The ECOG performance status at baseline was 0 or 1 in 96% of patients. The majority of patients had adenocarcinoma (95%) and never smoked (59%). CNS metastases were present in 26% (n=78) of patients: of these, 30 patients had measurable CNS lesions.

A planned interim analysis2 (median duration of follow-up for PFS of 18.3 months for lorlatinib and 14.8 months for crizotinib) was conducted. Two unplanned follow-up analyses were also completed.4,5

Study B7461006; NCT03052608.Including recent (within the past year) or active suicidal ideation or behavior.Assessed by BICR according to RECIST v1.1.BICR=Blinded Independent Central Review; BID=twice daily; CNS=central nervous system; ECOG PS=Eastern Cooperative Oncology Group performance status; QD=once daily; RECIST v1.1=Response Evaluation Criteria in Solid Tumors version 1.1.Progression-Free Survival Start with LORBRENA First-Line for Appropriate Patients: Superior Progression-Free Survival vs Crizotinib
  • At the data cut-off, OS data were not mature; there were not enough events to calculate median OS2
Based on 1-sided stratified log-rank test.HR=hazard ratio; PFS=progression-free survival. Median Progression-Free Survival Not Reached at 5 Years of Follow-up LIMITATIONS: The results of this unplanned, investigator-assessed analysis are descriptive. No formal hypothesis testing was performed.4
  • 81% reduction (HR=0.19 [95% CI: 0.13-0.27]) in risk of progression or death vs crizotinib (Investigator-assessed)4
Overall and Intracranial Response Rates Overall Response Rate (ORR)
  • Median DOR (range): Not reached (0.9-31.3) with LORBRENA vs 11 months (1.1-27.5) with crizotinib
  • Response duration ≥12 months: 70% with LORBRENA vs 27% with crizotinib
Assessed by BICR according to RECIST v1.1. Intracranial ORR in Patients with Measurable Brain Metastases at Baseline#
  • Response duration ≥12 months: 79% with LORBRENA vs 0% with crizotinib
Assessed by BICR according to RECIST v1.1.Intracranial response and duration of response were evaluated in a prespecified exploratory analysis of 30 patients (31 patients in the follow-up analysis) with measurable CNS lesions at baseline.BICR=Blinded Independent Central Review; CNS=central nervous system; DOR=duration of response; ORR=overall response rate. Overall and Intracranial Response Rates in a 3-Year Follow-up Analysis An unplanned analysis was performed at median follow-up of 36.7 months for patients on LORBRENA (29.3 months for patients on crizotinib). No formal hypothesis testing was performed; results are presented descriptively.5 77% Overall ORR||
  • Median DOR: Not reached (95% CI: NR-NR) with LORBRENA vs 9.6 months (95% CI: 9.0-12.9) with crizotinib5
Assessed by BICR per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.5 83% Intracranial ORRII in Patients with Measurable Brain Metastases at Baseline**
  • Median intracranial DOR: Not reached (95% CI: NR-NR) with LORBRENA vs 10.2 months (95% CI: 9.4-11.1) with crizotinib5
Assessed by BICR per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.5Intracranial response and DOR were evaluated in an exploratory analysis of 31 patients with measurable CNS lesions at baseline.5Median Time to Intracranial Progression Not Reached at 5 Years of Follow-up4††Median Time to Intracranial ProgressionLIMITATIONS: The results of this unplanned, investigator-assessed analysis are descriptive.4
  • Secondary endpoint of intracranial progression (IC-TTP) was not part of the statistical 
 testing hierarchy

  • Small number of patients with brain metastases at baseline is a limitation

  • Clinical relevance of these data is unknown because they do not include disease status in the rest of the body

  • Data for IC-TTP were not included in the USPI by the FDA
  • Median follow-up of 60.2 months for patients on LORBRENA vs 55.1 months for patients on crizotinib4
Time from randomization to the first objective progression of CNS disease (either new brain metastases or progression of existing brain metastases).4CNS=central nervous system; DOR=duration of response; ORR=overall response rate. In this analysis of IC-TTP, there were no events observed beyond 30 months in LORBRENA-treated patients.4 ReferencesRecondo G, Facchinetti F, Olaussen KA, Besse B, Friboulet L. Nat Rev Clin Oncol. 2018;15(11):694-708.Shaw AT, Bauer TM, de Marinis F, et al; CROWN Trial Investigators. N Engl J Med. 2020;383(21):2018-2029.Protocol for: Shaw AT, Bauer TM, de Marinis F, et al; CROWN Trial Investigators. N Engl J Med. 2020;383(21):2018-2029. doi:10.1056/NEJMoa2027187Data on file. Pfizer, Inc., New York, NY.Solomon BJ, Bauer TM, Mok TSK, et al. Efficacy and safety of first-line lorlatinib versus crizotinib in patients with advanced, ALK-positive non-small-cell lung cancer: updated analysis of data from the phase 3, randomised, open-label CROWN study. Lancet Respir Med. 2023;11(4):354-366.
Efficacy in Patients Who Received Prior ALK TKI TherapyStudy Design: Prior ALK TKI Study Design: Prior ALK TKI LORBRENA is a third-generation ALK inhibitor that was studied in a subgroup of patients who progressed on second-generation ALK inhibitors1*

Phase 1/2, non-randomized, dose-ranging, activity-estimating, single-arm, multicohort, multicenter trial2

The demographic characteristics across the 215 patients were: 59% female, 51% White, 34% Asian; the median age was 53 years (29 to 85 years) with 18% of patients ≥65 years. The ECOG performance status at baseline was 0 or 1 in 96% of patients. All patients had metastatic disease and 95% had adenocarcinoma. Brain metastases as identified by ICR were present in 69% of patients; of these, 60% had received prior radiation to the brain and 60% (n=89) had measurable disease per ICR.

ReferencesAlectinib, ceritinib, or brigatinib.1According to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 and as assessed by Independent Central Review (ICR) committee.ECOG=Eastern Cooperative Oncology Group. Prior Treatment ReferencesChemotherapy administered in the metastatic setting. Overall and Intracranial Response Rates

In exploratory analyses conducted in subgroups defined by prior therapy, the response rates to LORBRENA were:

  • ORR=39% (95% CI: 30-48) in 119 patients who received crizotinib and at least one other ALK inhibitor
  • ORR=31% (95% CI: 9-61) in 13 patients who received alectinib as their only ALK inhibitor
  • ORR=46% (95% CI: 19-75) in 13 patients who received ceritinib as their only ALK inhibitor
ReferencesAssessed by Independent Central Review (ICR) per RECIST version 1.1.Intracranial ORR and duration of response were assessed per ICR in a subgroup of 89 patients with measurable baseline lesions in the CNS according to RECIST version 1.1. Of these patients, 63% (n=56/89) received prior brain radiation, of whom 75% (n=42/56) completed brain radiation treatment at least 6 months before starting treatment with LORBRENA.With or without prior chemotherapy.CNS=central nervous system; NR=not reached; ORR=overall response rate; RECIST=Response Evaluation Criteria in Solid Tumors.ReferencesRecondo G, Facchinetti F, Olaussen KA, Besse B, Friboulet L. Nat Rev Clin Oncol. 2018;15(11):694-708.Data on file. Pfizer Inc., New York, NY.
Considerations for treatment selectionReferencesALK=anaplastic lymphoma kinase; CNS=central nervous system; TKI=tyrosine kinase inhibitor. ReferencesSchneider JL, Lin JJ, Shaw AT. ALK-positive lung cancer: a moving target. Nat Cancer. 2023;4(3):330-343.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.Rangachari D, Yamaguchi N, VanderLaan PA, et al. Brain metastases in patients with EGFR-mutated or ALK-rearranged non-small-cell lung cancers. Lung Cancer. 2015;88(1):108-111.Hizal M, Bilgin B, Sendur MA, et al. Evaluation of clinical features of ALK mutation-positive lung cancer patients receiving first-line alectinib therapy. Tuberk Toraks. 2021;69(3):321-327.
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INDICATION LORBRENA® (lorlatinib) 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.   

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 hepatic impairment. The recommended dose of LORBRENA has not been established for patients with moderate or severe hepatic impairment.

Renal Impairment: Reduce the dose of LORBRENA for patients with severe renal impairment. No dose adjustment is recommended for patients with mild or moderate renal impairment.

Please see Full Prescribing Information.

Indication

LORBRENA® (lorlatinib) 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.