Evaluating First-Line TKIs in ALK-Positive NSCLC: Insights From a Large Real-World Analysis
Key Takeaways
- Study rationale: Dr Rahul Mudumba discusses the need for real-world evidence in ALK-positive non–small cell lung cancer (NSCLC), where NCCN guidelines currently recommend four category 1 preferred first-line therapies due to a lack of definitive head-to-head comparisons.
- Research approach: Using a large U.S. real-world data set, the study evaluated the comparative effectiveness of four ALK-targeted therapies, addressing a key evidence gap in a rare disease setting.
- Clinical implications: The findings reinforce existing evidence supporting alectinib over crizotinib and demonstrate that trial results remain consistent in a more diverse, comorbidity-rich real-world population, helping reduce uncertainty in treatment selection.
In Part 1 of this interview, Rahul Mudumba, PhD, a health economist at the University of Southern California, discusses his research on health economics, outcomes research, and value assessment in oncology. Dr Mudumba explains the rationale behind his study evaluating first-line targeted therapies for ALK-positive NSCLC, a setting in which clinical guidelines currently recommend multiple preferred treatment options. He also discusses how real-world evidence can help address gaps left by clinical trials and provide clinicians with greater confidence when making treatment decisions for diverse patient populations.
Rahul Mudumba, PhD: I'm Rahul Mudumba. I'm a health economist finishing up my PhD at the University of Southern California. A lot of my research has been in health economics and outcomes research. How can we get better methods at assessing value and effectiveness in healthcare? Broadly speaking, most of my work has been in the oncology domain across different tumor types and diseases. A lot of the nature of my work has been looking into what are the most effective cancer therapies in the real world, how valuable are they really, and how can we get better at determining these two factors?
Can you give some background about your study and what prompted you to undertake it?
Dr Mudumba: Our study is looking into the most effective targeted therapies for ALK-positive NSCLC in the US. What prompted it was previous work looking at assessing value in the long term, and I realized we have a kind of conundrum in the U.S. The NCCN, which tells you which therapies are recommended first line and second line and what clinicians should be starting patients on, is split in its consensus, where it recommends 4 category 1 preferred therapies, which almost never happens. Usually you have one clear winner based on clinical trials. Here, however, it is a rare disease, not a lot of evidence exists in the real world, and the clinical trials have failed to compare the leading 4 options head-to-head.
That creates a lot of clinical uncertainty as to what is the best therapy to start a patient on. It prompts the question of what is the best of these 4 options and in which circumstances, given that you have one opportunity to start patients on the right note before things get further complicated. Because evidence was scarce and real-world sample sizes are difficult to accrue, we took advantage of a great data set and decided to be among the first to provide a large real-world study employing robust methods to examine the comparative effectiveness of the 4 therapies, which nobody has done to this degree.
This real-world analysis shows alectinib outperforming crizotinib in both OS and TTNTD. How should clinicians reconcile these findings with existing clinical trial data when making first-line treatment decisions in ALK-positive NSCLC?
Dr Mudumba: To tackle the first point, we've had great trial evidence comparing alectinib to crizotinib, so this has already been established and become convention. Folks are usually starting patients on alectinib in the real world. But there is still uncertainty about whether the benefits seen under strict trial criteria hold in the real world, where patients face more comorbidities than they would in a trial. Trials generally have fitter patients with fewer clinical comorbidities. Clinicians may wonder whether those results translate to routine practice.
In our study, we relaxed some of those strict trial assumptions and showed that the findings hold to a similar degree as expected from the trial setting. That increases confidence in the comparison in the real world, where patients reflect a more heterogeneous, diverse, and representative population than those in the clinical trials that informed the guidelines. In that sense, the study reduces some uncertainty by relaxing those strict assumptions.
