Alecensa has survival edge in ALK+ NSCLC, Study Finds

The expanding number of targeted therapy options for ALK-positive non-small cell lung cancer (NSCLC) has created a new challenge for clinicians and payers: figuring out which one performs best in routine clinical practice. A real-world analysis, published online ahead of print in Lung Cancer, suggests that Alecensa (alectinib) continues to deliver a meaningful survival advantage over the older ALK inhibitor Xalkori (crizotinib), while a newer agent, Lorbrena (lorlatinib), may offer additional benefit.

ALK-positive NSCLC accounts for roughly 4% to 5% of lung cancer cases and is driven by rearrangements in the anaplastic lymphoma kinase gene. Over the past decade, ALK inhibitors have transformed outcomes for these patients, replacing chemotherapy as the standard first-line treatment for advanced disease. Several next-generation ALK inhibitors, including Alecensa, Lorbrena and Alunbrig (brigatinib), are now listed as first-line options in National Comprehensive Cancer Network guidelines.

“NCCN guidelines list four drugs as co-equal preferred options, but there's been no head-to-head trial or real-world comparison to differentiate among them, and our study is the first to provide that,” co-first author Rahul Mudumba, Ph.D., M.H.S., and a health economist at the University of Southern California, told Managed Healthcare Executive in an email interview.

“It's the largest claims-based comparative effectiveness study of first-line ALK tyrosine kinase inhibitors in ALK-positive non-small cell lung cancer in the U.S,” Mudumba said. “We're also among the first to generate real-world effectiveness estimates for the newer-generation lorlatinib [Lorbrena] and brigatinib [Alunbrig] specifically.”

Looking beyond clinical trial data, Mudumba and colleagues at USC’s Mann School of Pharmacy and Pharmaceutical Sciences and Schaeffer Center for Health Policy and Economics analyzed outcomes of 940 patients with ALK-positive NSCLC treated with first-line ALK inhibitors between 2016 and 2024 using an Optum claims database. The researchers compared overall survival (OS) and time-to-next-treatment or death (TTNTD), a real-world endpoint often used as a proxy for progression-free survival.

Among the patients included in the analysis, 449 were treated with Xalkori, 417 with Alecensa, 30 with Alunbrig and 36 with Lorbrena. Zykadia (ceritinib) recipients were excluded from comparative analyses because of the small sample size.

In unadjusted analyses, Alecensa demonstrated the longest reached median TTNTD at 33.5 months compared with 12.2 months for Xalkori. Median OS was also notably longer with Alecensa at 46.5 months versus 21.4 months with Xalkori. Lorbrena showed the most favorable survival trends overall, but median survival estimates were not reached because of limited follow-up and relatively few events.

After adjusting for baseline differences, Alecensa remained associated with significantly better outcomes than Xalkori. Patients treated with Alecensa had a 42% lower risk of death and a 50% lower risk of switching to another treatment or death compared with those receiving Xalkori.

Comparisons between Alecensa and Lorbrena were less definitive. Results slightly favored Lorbrena for TTNTD, but the differences were not statistically significant. The authors noted that the small number of Lorbrena-treated patients and shorter follow-up likely limited the precision of those findings.

The researchers noted that the results generally aligned with prior randomized trials, including the ALEX study that compared Alecensa with Xalkori. They also said the analysis adds important real-world evidence to a field where head-to-head comparisons among preferred ALK inhibitors are in short supply.

The study has several limitations typical of claims-based research. The investigators relied on diagnosis codes and pharmacy claims to identify ALK-positive NSCLC, which may have introduced some misclassification. The population also primarily included commercially insured and Medicare Advantage patients, potentially limiting generalizability to uninsured or Medicaid populations. Small sample sizes for Alunbrig and Lorbrena further reduced the certainty of some comparisons.

Still, the authors said the findings help reinforce Alecensa’s role as a first-line standard of care while highlighting Lorbrena as a potentially promising option as more real-world data become available. They added that larger future analyses may help clarify optimal sequencing strategies among the growing number of ALK-targeted therapies.

“This is especially consequential given the fact that it's a rare disease with very limited real-world evidence, and as MHE previously reported, costs are extremely substantial and recurring,” Mudumba said.