Lung cancer is the number one cause of cancer-related death around the world. NSCLC accounts for approximately 80-85% of lung cancers, with ALK-positive tumors occurring in about 3 to 5% of NSCLC cases. Targeted medicine has changed the treatment of ALK+ NSCLC by blocking the action of the altered ALK gene to help shrink brain, liver, and bone progression. Brain metastases, in particular, can affect up to 50% of patients with ALK+ NSCLC. In 2018, the U.S. Food and Drug Administration (FDA) approved LORBRENA for the treatment of patients with ALK-positive metastatic NSCLC whose disease has progressed on crizotinib and at least one other ALK inhibitor for metastatic disease; or whose disease has progressed on alectinib or ceritinib as the first ALK inhibitor therapy for metastatic disease. This indication is approved under accelerated approval based on tumor response rate and duration of response.
CROWN is the confirmatory study for the conversion to full approval, and based on the results of the CROWN trial, Pfizer intends to share the results with the FDA and other health authorities to support conversion to full approval and to seek approval for an indication that includes previously untreated ALK-positive metastatic NSCLC.
Lorlatinib is a highly potent, brain-penetrant, third-generation ALK TKI with overall and also intracranial (IC) activity in advanced ALK+ NSCLC. Pfizer has presented the planned interim analysis from the CROWN study in ESMO virtual conference 2020 as Late-Breaking Abstract #17. CROWN is a phase 3, randomized, open-label study comparing lorlatinib vs. crizotinib as the first-line treatment option in patients with advanced ALK+ NSCLC across 104 study sites in 23 countries. Lorlatinib significantly improved progression-free survival compared with crizotinib and led to a 72% improvement in PFS by BICR compared with crizotinib (hazard ratio [HR] 0.28). Median PFS times for lorlatinib were not estimable (NE) and 9.3 months for crizotinib. Besides, the 12-month PFS rate was 78% and 39% for those receiving lorlatinib and crizotinib, respectively. The ORR rates by BICR were 76% and 58% in patients treated with lorlatinib and crizotinib, respectively, and, with the exception of a 3% complete response (CR) rate in patients treated with lorlatinib, almost all responses were partial. IC-OR rates by BICR were 82% vs. 23% for patients with measurable brain metastases at baseline treated with lorlatinib compared with crizotinib, respectively. And a particularly notable finding where CR rates in loratinib subgroup of patients were 71% compared with 8% for patients treated with crizotinib. The incidence of grade 3/4 adverse events (AEs) was higher with lorlatinib (72.5%) than crizotinib (55.6%), with the majority of AEs in the lorlatinib arm being laboratory abnormalities (mainly lipid abnormalities)
Lorlatinib showed promising efficacy as a first-line treatment option and resulted in a significantly longer PFS, significantly higher overall and IC response rates, and improved global QoL compared to crizotinib in ALK+ NSCLC patients. And the interim data indicate the ability of lorlatinib in not only in delaying the progression of existing brain metastases but also in preventing the development of new brain metastases in patients with ALK-positive NSCLC. The above data support the lorlatinib peak share estimated on DelveInsight’s report titled “ALK+ Non-small cell lung cancer (NSCLC) -Market Insights, Epidemiology, and Market Forecast-2030.”