KEY TAKEAWAYS
- The phase 3 CROWN trial aimed to evaluate the efficacy of lorlatinib compared to crizotinib in terms of progression-free survival and objective response rate.
- Patients were randomly assigned to receive either 100 mg of oral lorlatinib daily or 250 mg of oral crizotinib twice daily.
- Lorlatinib was superior to crizotinib in terms of progression-free survival, objective response rate, intracranial objective response rate, time to intracranial progression, and response length.
- Baseline brain metastases status was used to evaluate efficacy outcomes, and lorlatinib was associated with fewer adverse events than crizotinib.
- The study showed that lorlatinib significantly improved progression-free survival, objective response rate, and intracranial objective response rate.
Patients with treatment-naive, ALK-positive non-small-cell lung cancer (NSCLC) improved progression-free survival (PFS) after receiving lorlatinib, a third-generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor, in the phase 3 CROWN trial. The researchers described updated efficacy results after 3 years of follow-up, including intracranial activity in the CROWN study conducted at 104 sites across 23 countries as a randomized, open-label, third-phase trial. Patients with advanced ALK-positive NSCLC, no prior systemic treatment for metastatic disease, at least one extracranial measurable target lesion (according to Response Evaluation Criteria in Solid Tumors [RECIST], version 1.1), and an Eastern Cooperative Oncology Group performance status of 0-2 were eligible to participate. Patients received either 100 mg of oral lorlatinib daily or 250 mg of oral crizotinib twice daily, in cycles lasting 28 days. Brain metastasis status and race were used to determine how participants would be randomly assigned. After the primary endpoint reached the intermediate analysis, the protocol called for no further formal examination of progression-free survival. An ad hoc analysis was conducted to characterize tumor-related endpoints with a longer follow-up. Progression-free survival, as determined by a central, independent, blinded review, was the trial’s primary endpoint. Objective response rate, intracranial objective response rate, time to intracranial progression, duration of response, course of response in the brain, and safety were secondary objectives. Baseline brain metastases status was also used to evaluate efficacy outcomes.
A total of 425 patients were screened between May 11, 2017, and February 28, 2019, with 296 ultimately enrolling to receive either lorlatinib (n=149) or crizotinib (n=147). The median progression-free survival for lorlatinib was 36.7 months (interquartile range [IQR] 31.3-41.9) as per the September 20, 2021 data cutoff date. For crizotinib, it was 29.5 months (IQR 10.8-35.0). Independent central evaluation revealed that the median PFS for lorlatinib was not attained (95% confidence interval [CI]: not reached-not reached), while PFS for crizotinib was 9.3 months (7.6-11.1) (hazard ratio [HR]: 0.27 [95% CI: 0.18-0.39]). The lorlatinib group had a 3-year PFS of 64% (95% CI 55-71) compared to the crizotinib group’s PFS of 19% (12-27). Lorlatinib was superior to crizotinib in PFS (investigator), objective response rate, intracranial objective response rate, time to intracranial progression, and response length. The HR for time to intracranial progression for lorlatinib versus crizotinib was 0.10 (95% CI 0.04 to 0.27) in patients with baseline brain metastases (n=37 lorlatinib, n=39 crizotinib), and it was 0.02 (95% CI 0.002 to 0.14) in patients without baseline brain metastases (n=112 lorlatinib, n=108 crizotinib). One patient in the lorlatinib group (1%) and 25 individuals in the crizotinib group (23%) developed intracranial progression despite not having brain metastases. Among 149 patients, 113 (76%) experienced adverse effects of grade 3-4 (most typically owing to changed lipid levels) while taking lorlatinib, and among the 142 patients taking crizotinib, 81 (57%) experienced the same. Eleven (7%) patients in the lorlatinib group and fourteen (10%) individuals in the crizotinib group discontinued treatment due to adverse events. No updated warning signs were present.
Source:https://pubmed.ncbi.nlm.nih.gov/36535300/
Clinical Trial:https://clinicaltrials.gov/ct2/show/NCT03052608
Solomon BJ, Bauer TM, Mok TSK, Liu G, Mazieres J, de Marinis F, Goto Y, Kim DW, Wu YL, Jassem J, López FL, Soo RA, Shaw AT, Polli A, Messina R, Iadeluca L, Toffalorio F, Felip E. 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, randomized, open-label CROWN study. Lancet Respir Med. 2023 Apr;11(4):354-366. doi: 10.1016/S2213-2600(22)00437-4. Epub 2022 Dec 16. PMID: 36535300.
