Lorbrena Shows Longest Progression-Free Survival in Advanced NSCLC

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Lorbrena demonstrated longer progression-free survival and improved time to intracranial progression, compared with Xalkori in ALK-positive non-small cell lung cancer.

Patients with ALK-positive non-small cell lung cancer (NSCLC) had the longest progression-free survival (PFS; living without disease worsening or spreading) ever reported after receiving Lorbrena (lorlatinib).

Lorbrena data were compared with Xalkori (crizotinib) outcomes in the phase 3 CROWN trial. The five-year follow-up data from the trial were presented at the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting.

Study Highlights:

  • Lorbrena is a third-generation ALK-directed tyrosine kinase inhibitor (TKI). TKIs are drugs that block tyrosine kinase enzymes to prevent the growth of cancer cells.
  • The trial compared Lorbrena to Xalkori (crizotinib). Patients were randomly assigned to receive either Lorbrena daily or Xalkori twice daily.
  • The primary end point of the study was progression-free survival (PFS; living without disease worsening or spreading). Lorbrena showed a significantly longer PFS than Xalkori. The median PFS was not reached in the Lorbrena group, compared with 9.1 months in the Xalkori group. The five-year PFS rates were 60% versus 8%, respectively.
  • Lorbrena was also well tolerated with no new safety signals reported.
  • More data is needed on overall survival (OS; time patients are alive, regardless of disease status). Follow-up is ongoing as insufficient survival events have been reached to trigger the protocol-specified analysis for OS.

“These results represent the most significant PFS benefit that has been reported in ALK-positive lung cancer to date,” Benjamin J. Solomon, a medical oncologist atPeter MacCallum Cancer Centre in Melbourne, Australia, said in a presentation of the data.

Patients were randomly assigned evenly among two groups to receive either Lorbrena daily or Xalkori twice daily. The primary end point of the study (main result measured to see if treatment worked) was PFS, as determined by an independent panel of experts who do not know which patients received which treatments. Secondary end points included overall survival (OS; time patients are alive, regardless of disease status), PFS as determined by the study investigators, safety and objective response rate (percentage of patients whose disease shrunk or disappeared), among others.

The trial enrolled patients with stage 3B/4 ALK-positive NSCLC who had not received prior systemic treatment for metastatic disease. Patients had an ECOG performance status of 2 or less — meaning they were able to physically function independently — and at least one extracranial measurable target lesion (targetable tumor outside of the skull) with no prior radiation required. Patients with asymptomatic treated or untreated central nervous system metastases were also eligible. Additionally, patients were not allowed to crossover from one treatment regimen to the other.

Treatment with Lorbrena, a third-generation ALK-directed tyrosine kinase inhibitor (TKI; drug that blocks tyrosine kinase enzymes to prevent the growth of cancer cells), also resulted in benefit across patient subgroups, regardless of presence of brain metastases (cancer spread to the brain), ethnic origin, sex, age and smoking status.

Findings from the study revealed that the median PFS was not reached in the Lorbrena group of 149 patients, indicating that not enough patients experienced disease progression for the researchers to calculate an average. This was compared with 9.1 months in the Xalkori group of 147 patients. The five-year PFS rates were 60% versus 8%, respectively, with a median duration of follow-up for PFS of 60.2 months in the Lorbrena group versus 55.1 months in the Xalkori group. No new safety signals were reported with Lorbrena.

“The PFS is outstanding; we have not seen anything close to this. Other great drugs that are available including [Alecensa (alectinib)] and [Alunbrig (brigatinib)] have not reported durable PFS events of this magnitude,” Dr. David R. Spigel, a medical oncologist and the chief scientific officer at Sarah Cannon Research Institute in Nashville, Tennessee, added in a discussion of the data.

There were 35 patients treated with Lorbrena who had brain metastases at baseline and had not reached a median PFS. This was compared with 38 patients in the Xalkori group who had a median PFS of six months. Patients without brain metastases at baseline in the Lorbrena group (114 patients) had not reached a median PFS, compared with 10.8 months for patients in the Xalkori group; (109 patients) the five-year PFS rates were 63% versus 10%, respectively.

“This study was originally reported in 2020 after 18 months of follow-up and was positive for its primary end point … and a median PFS that had not been reached with [Lorbrena]. On the basis of these initial results, [Lorbrena] was approved as first-line treatment globally [in March 2021],” Solomon added.

Solomon also noted that time to intracranial progression (disease worsening or spreading inside the skull) was longer with Lorbrena compared with Xalkori in the presence or absence of brain metastases.

In patients with brain metastases, the median time to intracranial progression was not reached in the Lorbrena group, versus 7.2 months in the Xalkori group. The median time to intracranial progression was not reached versus 23.9 months, respectively, in patients without brain metastases and 96% versus 27%, respectively, did not experience intracranial progression at five years.

Solomon added that progressive central nervous system involvement remains a key concern, because approximately 25% of patients with ALK-positive NSCLC have brain metastases at baseline.

“These results speak to the ability of [Lorbrena] not only to prevent progression of existing brain metastases, but to prevent or delay progression of new brain metastases,” Solomon said. “The systemic efficacy results coupled with prolonged intracranial efficacy from first line [Lorbrena] treatment indicate that this provides an unprecedented improvement in outcomes for patients with advanced ALK-positive NSCLC.”

Spigel added that treatment with Xalkori is not as widespread as it once was, and Lobrena has not yet been studied in comparison with other TKIs.

“[In] this trial the comparator arm was [Xalkori, which is] still used in some parts of the world [but it] is not really used in the United States much at all anymore; [it was] an outstanding drug at its time, but better drugs are available now. With that said, the results with [Lorbrena] are the best we’ve ever seen. It’s not good to compare studies [with] other studies, we have not had a randomized controlled trial of [Lorbrena] versus another modern next-generation TKI, but these are among the best [data in this patient population that] we’ve ever seen.”

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