Pfizer Inc. (NYSE: PFE) today announced longer-term follow-up results from the Phase 3 CROWN trial evaluating LORBRENA® (lorlatinib, a third-generation ALK inhibitor, available in Europe under the brand name LORVIQUA®) versus XALKORI® (crizotinib) in people with previously untreated, anaplastic lymphoma kinase (ALK)-positive advanced non-small cell lung cancer (NSCLC). After five years of median follow-up, median progression-free survival (PFS) based on investigator assessment was not reached with LORBRENA, with an observed Hazard Ratio (HR) of 0.19 (95% Confidence Interval [CI], 0.13-0.27), representing an 81% reduction in the rate of disease progression or death compared to XALKORI. Further, 60% of patients treated with LORBRENA (95% CI, 51-68) were alive without disease progression after five years compared to 8% (3-14) on the XALKORI treatment arm. These data will be presented today in an oral presentation at the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting (Abstract LBA8503) and have been simultaneously published in the Journal of Clinical Oncology.
"These results from the CROWN trial are unprecedented, as the majority of patients on LORBRENA are living beyond five years without disease progression," said Roger Dansey, M.D., Chief Development Officer, Oncology, Pfizer. "These results are an excellent example of Pfizer’s long-standing commitment to discovering and developing scientific breakthroughs for patients, and support LORBRENA as a standard of care for the first-line treatment of people with ALK-positive advanced NSCLC."
Lung cancer is the number one cause of cancer-related death around the world,(1) and an estimated 234,580 new cases of lung cancer are expected to be diagnosed in the U.S. in 2024.(2) NSCLC accounts for approximately 80-85% of lung cancers,(3) with ALK-positive tumors occurring in about 3-5% of NSCLC cases.(4) Approximately 25-40% of people with ALK-positive advanced NSCLC may develop brain metastases within two years from initial diagnosis.(5) LORBRENA was specifically designed and developed by Pfizer to inhibit tumor mutations that drive resistance to other ALK inhibitors and to penetrate the blood-brain barrier.
"ALK-positive advanced NSCLC is typically aggressive and often impacts younger people in the prime of their lives," said Benjamin Solomon, MBBS, Ph.D., Department of Medical Oncology, Peter MacCallum Cancer Centre, and Principal Investigator of the CROWN trial. "This updated analysis shows that LORBRENA helped patients live longer without disease progression, with the majority of patients experiencing sustained benefit for over five years, including nearly all patients having protection from progression of disease in the brain. These improvements in outcomes for patients with ALK-positive NSCLC represent a remarkable advancement in lung cancer."
In this updated analysis, LORBRENA showed a 94% reduction in the risk of developing intracranial (IC) progression (HR, 0.06; 95% CI, 0.03-0.12). The median time to IC progression was not reached (95% CI, NR-NR) with LORBRENA and was 16.4 months (12.7-21.9) with XALKORI. In people without brain metastases at baseline receiving LORBRENA, only 4 of 114 developed brain metastases within the first 16 months of treatment, compared to 39 of 109 patients who received XALKORI. At the time of analysis, 50% of patients in the CROWN trial were still receiving LORBRENA compared to 5% of patients receiving XALKORI.
"Although ALK-positive advanced NSCLC accounts for only approximately five percent of all NSCLC cases, this translates to 72,000 people who are diagnosed worldwide each year," said Kenneth Culver, M.D., Director of Research and Clinical Affairs at the non-profit organization ALK Positive. "These new results of the CROWN trial symbolize significant progress in the first-line setting for the targeted treatment of ALK-positive lung cancer, which has led to notable improvements for the patient community."
The safety profiles of LORBRENA and XALKORI in the five-year follow-up were consistent with previous findings, with no new safety signals reported for LORBRENA. In this analysis, the most frequent (≥20%) adverse events (AEs) reported in patients treated with LORBRENA were consistent with the 2020 analysis of the CROWN trial, which included edema, weight gain, peripheral neuropathy, cognitive effects, mood effects, diarrhea, dyspnea, arthralgia, hypertension, headache, cough, pyrexia, hypercholesterolemia, and hypertriglyceridemia. Grade 3/4 AEs occurred in 77% of patients with LORBRENA and in 57% of patients with XALKORI. Treatment-related AEs led to permanent treatment discontinuation in 5% and 6% of patients in the LORBRENA and XALKORI arms, respectively.
Pfizer is continuing its commitment to help non-scientists understand the latest findings with the development of abstract plain language summaries (APLS) for company-sponsored research being presented at ASCO, which are written in non-technical language. Those interested in learning more can visit www.Pfizer.com/apls to access the summaries.
About the CROWN Trial CROWN is a Phase 3, randomized, open-label, parallel 2-arm trial in which 296 people with previously untreated ALK-positive advanced NSCLC were randomized 1:1 to receive LORBRENA monotherapy (n=149) or XALKORI monotherapy (n=147). The primary endpoint of the CROWN trial is PFS based on Blinded Independent Central Review (BICR). Secondary endpoints include PFS based on investigator's assessment, overall survival (OS), objective response rate (ORR), intracranial objective response (IOR), and safety. Given that median PFS was not reached after three years of follow-up, an unplanned post hoc analysis was executed with the intent to further quantify long-term outcomes based on investigator tumor assessment from this study at a clinically meaningful landmark follow-up of five years.
About LORBRENA® (lorlatinib)
LORBRENA is approved in the U.S. for the treatment of adults with metastatic NSCLC whose tumors are ALK-positive as detected by an FDA-approved test.Please see Full Prescribing Information for LORBRENA® (lorlatinib) or visit https://www.lorbrena.com
About Pfizer Oncology
At Pfizer Oncology, we are at the forefront of a new era in cancer care. Our industry-leading portfolio and extensive pipeline includes three core mechanisms of action to attack cancer from multiple angles, including small molecules, antibody-drug conjugates (ADCs), and bispecific antibodies, including other immune-oncology biologics. We are focused on delivering transformative therapies in some of the world’s most common cancers, including breast cancer, genitourinary cancer, hematology-oncology, and thoracic cancers, which includes lung cancer. Driven by science, we are committed to accelerating breakthroughs to help people with cancer live better and longer lives.
About Pfizer: Breakthroughs That Change Patients' Lives
At Pfizer, we apply science and our global resources to bring therapies to people that extend and significantly improve their lives. We strive to set the standard for quality, safety and value in the discovery, development, and manufacture of health care products, including innovative medicines and vaccines. Every day, Pfizer colleagues work across developed and emerging markets to advance wellness, prevention, treatments, and cures that challenge the most feared diseases of our time. Consistent with our responsibility as one of the world's premier innovative biopharmaceutical companies, we collaborate with health care providers, governments, and local communities to support and expand access to reliable, affordable health care around the world. For more than 175 years, we have worked to make a difference for all who rely on us.
1. World Health Organization. International Agency for Research on Cancer. GLOBOCAN 2022: DOI: 10.3322/caac.21834. Global Population Fact sheet: https://gco.iarc.who.int/media/globocan/factsheets/populations/900-world-fact-sheet.pdf
2. American Cancer Society. Key Statistics for Lung Cancer. https://www.cancer.org/cancer/types/lung-cancer/about/key-statistics.html Access April 2024.
3. American Cancer Society. What is lung cancer? https://www.cancer.org/cancer/lung-cancer/about/what-is.html Accessed June 2024.
4. Garber K. ALK, lung cancer, and personalized therapy: portent of the future? J Natl Cancer Inst. 2010;102:672-675.
5. 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 DOI: 10.1016/j.lungcan.2015.01.020