A team of researchers from the Keck School of Medicine of USC, the USC Alfred E. Mann School of Pharmacy and Pharmaceutical Sciences and the USC Shaeffer Center for Health Policy & Economics have conducted a head-to-head comparison of five leading treatments for anaplastic lymphoma kinase-positive (ALK+) non-small cell lung cancer. It is the first study to analyze two new drugs, lorlatinib and brigatinib, outside of clinical trials. The findings, just published in the journal Lung Cancer, could help patients and physicians make more informed decisions about treatment.
ALK+ lung cancer, in which the ALK gene fuses with another gene, makes up about 4% of lung cancer diagnoses and often affects patients with little to no smoking history. The mutation leads to the creation of a faulty protein that drives the cancer cells to grow and multiply. Treatment typically involves ALK tyrosine kinase inhibitors (TKIs), a type of targeted therapy that prevents the growth and spread of cancer cells by blocking the faulty protein.
But with several TKIs now approved by the Food and Drug Administration for the initial, or first-line, treatment of ALK+ lung cancer, choosing the best option can be a challenge. Current guidelines from the National Comprehensive Cancer Network (NCCN) equally recommend four TKIs for first-line treatment of advanced ALK+ lung cancer, but clinical trials may not fully capture how they perform in broader groups of patients.
"Clinical trial data are great, but they come from a very narrow and curated group of patients who don't look like most of the patients we actually treat," said Jorge J. Nieva, MD, professor of clinical medicine at the Keck School of Medicine and the study's senior author. "Real-world studies like this one are important because they tell us what happens when drug therapy is applied to a much broader patient population."
Nieva and his colleagues used insurance claims data from 940 patients to compare five TKIs for ALK+ lung cancer: crizotinib, alectinib, lorlatinib, brigatinib and ceritinib (which is not a preferred NCCN treatment). For each patient, they calculated overall survival and the length of time until there was a change in treatments, indicating that the drug had stopped working or was not well tolerated, or the patient died. The analysis found that alectinib showed the clearest survival advantage, with early data pointing to potential benefits with lorlatinib for some patients.
Real-world realities
For the study, researchers used data from Optum's Clinformatics Data Mart database, which includes anonymous insurance claims data from patients across the United States.
This type of data adds important context to results from clinical trials, which are usually done under carefully controlled conditions to help researchers clearly pinpoint the effects of a treatment. But the tight parameters of clinical trials do not always match real-world realities.
"The conditions that allow researchers to make those clean comparisons can also make clinical trial findings less representative of the patients doctors actually treat," said Rahul Mudumba, PhD, a researcher in the Mann School's Department of Pharmaceutical and Health Economics, who is co-first author of the study along with Xiaofan Liu, also of the Mann School. For example, clinical trials of ALK-targeted therapies generally do not include patients with poor overall health or other serious medical conditions, even though these circumstances are common.
In the present study, researchers included data from 940 patients who were treated for ALK+ lung cancer between 2016 and 2024. Of those, 449 received crizotinib, the first ALK-targeted TKI approved by the FDA in 2011; 8 received ceritinib, a second-generation TKI; 417 received alectinib, a widely adopted second-generation TKI that was FDA-approved in 2015; 30 received brigatinib, another second-generation TKI; and 36 received lorlatinib, a third-generation TKI.
Patients taking alectinib tended to survive the longest, with a median survival of 46.5 months, and stay on the treatment the longest, with a median of 33.5 months. Compared to crizotinib, alectinib performed better on both measures. Early findings suggested lorlatinib may offer additional benefits over alectinib, but the results were not statistically significant.
"The study tells us that the benefits of newer TKIs also apply to patients excluded from clinical trials, including those who are older or have multiple conditions," Nieva said.
Defining the standard of care
The findings can help physicians and patients make informed choices about care, balancing data on side effects, risk and overall effectiveness. For example, lorlatinib appears to work very well for some patients but less consistently across patient groups, whereas alectinib may provide more uniform outcomes. Treatment decisions may vary based on a patient's cancer stage, overall health, and personal tolerance for risk and side effects.
More data is needed on brigatinib and lorlatinib to know which treatment is most effective. A similar analysis conducted in one to two years could provide enough evidence to influence NCCN guidelines, Mudumba said.
"With larger real-world datasets, this type of research could eventually help redefine the standard of care," he said.
About this research
In addition to Nieva, Mudumba and Liu, the study's other authors are Shihan Jin, Ian J. Davis and John A. Romley from the Department of Pharmaceutical and Health Economics, Alfred E. Mann School of Pharmacy and Pharmaceutical Sciences, University of Southern California; and Drishti Baid from the Sol Price School of Public Policy, University of Southern California.
Disclosure: Unrelated to this work, Nieva has received funding from Aadi Biosciences, ANP Technologies, Astra Zeneca, BioAtla, BMS, Catalym, Daiichi Sankyo, Gilead, Genentech, Kalivir, Merck, Merus, Sanofi, Pfizer, Takeda, Tubulis and Urogen.
