On January 28, 2022 Pfizer Inc. (NYSE: PFE) reported that the European Commission (EC) granted marketing authorization for LORVIQUA (lorlatinib, available in the U.S. under the brand name LORBRENA) as monotherapy for the treatment of adult patients with anaplastic lymphoma kinase (ALK)- positive advanced non-small cell lung cancer (NSCLC) previously not treated with an ALK inhibitor (Press release, Pfizer, JAN 28, 2022, View Source [SID1234607488]).
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"For more than a decade, Pfizer has worked tirelessly in its pursuit to help transform the trajectory for people living with advanced, biomarker-driven lung cancers," said Andy Schmeltz, Global President & General Manager, Pfizer Oncology. "The European Commission’s approval of LORVIQUA as a first-line therapy is a significant milestone that we hope will help bring a needed and meaningful difference to those impacted by this deadly disease in Europe."
The approval for the first-line use of LORVIQUA was based on the results of the pivotal Phase 3 CROWN trial, in which LORVIQUA reduced the risk of disease progression or death by 72% compared to XALKORI (crizotinib). As a secondary endpoint, the confirmed objective response rate (ORR) was 76% (95% CI, 68 to 83) with LORVIQUA and 58% (95% CI, 49 to 66) with XALKORI. In patients with measurable brain metastases, 82% of patients in the LORVIQUA arm experienced an intracranial response (71% had an intracranial complete response), compared to 23% of XALKORI patients. The CROWN trial is a randomized, open-label, parallel 2-arm trial in which 296 people with previously untreated advanced ALK-positive NSCLC were randomized 1:1 to receive LORVIQUA monotherapy (n=149) or XALKORI monotherapy (n=147).
"The expanded approval for LORVIQUA in Europe is a considerable advancement – especially for the close to 40 percent of patients with ALK-positive metastatic NSCLC who are faced with brain metastases at diagnosis," said Professor Benjamin Solomon, MBBS, PhD., Department of Medical Oncology at the Peter MacCallum Cancer Centre in Melbourne, Australia. "It is exciting to see the significant data generated from the CROWN trial continuing to support expanded use around the world and providing physicians in Europe with a highly effective option from the onset of their patients’ treatment journey."
The EC approval of LORVIQUA follows a positive opinion from the Committee for Medicinal Products for Human Use (CHMP) in December 2021. LORVIQUA is approved in the U.S. by the Food and Drug Administration (FDA) under the brand name LORBRENA for the treatment of adults with metastatic NSCLC whose tumors are ALK-positive as detected by an FDA-approved test. In 2019, the EC granted conditional marketing authorization for LORVIQUA as a monotherapy for the treatment of adult patients with ALK-positive advanced NSCLC whose disease has progressed after alectinib or ceritinib as the first ALK tyrosine kinase inhibitor (TKI) therapy, or crizotinib and at least one other ALK TKI.
About the CROWN Trial of LORVIQUA
In the CROWN trial, patients were required to have an ECOG performance status of 0-2 and ALK-positive NSCLC as identified by the VENTANA ALK (D5F3) CDx assay. The primary endpoint of the CROWN trial was progression-free survival (PFS) based on blinded independent central review (BICR). Secondary endpoints included overall survival (OS) and tumor assessment related data by BICR, including ORR, and duration of response (DOR). In patients with measurable central nervous system (CNS) metastases at baseline, additional outcome measures were intracranial (IC)-ORR and IC-DOR by BICR. The trial is continuing in order to further evaluate the secondary endpoint of OS, which was not mature at the time of analysis.
Overall, the safety profile of LORVIQUA was similar to that reported in previous studies. The most frequent adverse events (AEs) in ≥20% of 149 patients treated with LORVIQUA were edema, weight gain, peripheral neuropathy, cognitive effects, diarrhea, dyspnea and hypertriglyceridemia. Serious AEs occurred in 34% of people treated with LORVIQUA; the most frequently reported serious AEs were pneumonia, dyspnea, respiratory failure, cognitive effects and pyrexia. Fatal AEs occurred in 3.4% of people treated with LORVIQUA. Permanent discontinuation of LORVIQUA due to AEs occurred in 6.7% of people. Detailed results from the CROWN study were published in the November 2020 issue of the New England Journal of Medicine.
About Non-Small Cell Lung Cancer (NSCLC)
Lung cancer is the number one cause of cancer-related death around the world.1 NSCLC accounts for approximately 80-85% of lung cancers,2 with ALK-positive tumors occurring in about 3-5% of NSCLC cases.3 Up to 40% of people with ALK-positive metastatic NSCLC present with brain metastases at initial diagnosis.4,5,6
About LORVIQUA (lorlatinib)
LORVIQUA is a TKI that has been shown to be highly active in preclinical lung cancer models harboring chromosomal rearrangements of ALK. LORVIQUA was specifically developed to inhibit tumor mutations that drive resistance to other ALK inhibitors and to penetrate the blood brain barrier.
The full U.S. prescribing information for LORBRENA can be found here.
IMPORTANT LORBRENA (lorlatinib) SAFETY INFORMATION FROM THE U.S. PRESCRIBING 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.