Evaluating First-Line TKIs in ALK-Positive NSCLC: Insights From a Large Real-World Analysis: Part 2
Key Takeaways:
- Interpreting lorlatinib data: Early real-world findings suggest lorlatinib may offer favorable outcomes compared with alectinib, particularly in patients with more aggressive disease, but limited sample sizes and wide confidence intervals prevent definitive conclusions.
- Value of real-world evidence: Real-world studies can help clinicians differentiate among ALK tyrosine kinase inhibitors (TKIs) by providing insights into more diverse patient populations than those typically represented in clinical trials, supporting more individualized treatment decisions.
- Future research needs: Although this represents one of the largest US real-world analyses in ALK-positive non–small cell lung cancer (NSCLC), additional follow-up and larger samples for newer agents such as lorlatinib and brigatinib are needed to better inform future clinical guidelines.
In Part 2 of our interview with Rahul Mudumba, PhD, he discusses the implications of emerging real-world evidence for treatment selection among ALK-targeted therapies in ALK-positive NSCLC. He explores how clinicians should interpret promising but still uncertain findings for lorlatinib, the role of real-world data in differentiating therapies beyond clinical trial populations, and the additional research needed to inform future guideline development and optimize patient care.
Given that lorlatinib demonstrated directionally favorable outcomes, but with wide confidence intervals, how should oncologists interpret and incorporate this level of uncertainty into clinical pathways or treatment sequencing?
Rahul Mudumba, PhD: The main thing to preface is that if someone can take our analysis and involve a new cut of data within 1 year or 2 using the same methods, I think that could change things quite dramatically and potentially influence guidelines. Because our study is limited by a small sample size for lorlatinib, we can only make certain claims. In an exploratory sense, we do see outcomes trending in the right direction, with lorlatinib showing favorable outcomes vs alectinib when we mitigate a lot of the confounding we see in the real world. That said, we cannot make definitive claims yet, but these are some of the first estimates suggesting a possible upside.
Beyond simply needing more data, the wider spread of outcomes and lower certainty may indicate that for patients with more progressive or aggressive disease, there could be some upside to lorlatinib that might not have been apparent with alectinib or an earlier-generation TKI. It shows something we have not yet seen in the real world and provides a head-to-head comparison that previously was not available. We just cannot make definitive claims at this point. Additional data would be warranted, but these findings may still be informative to clinicians looking at representative patient populations in the first-line setting.
With multiple TKIs occupying similar positions in current guidelines, how might these real-world findings influence differentiation among agents and institutional clinical pathways?
Dr Mudumba: The main point is that you can get more granular with patient characteristics than what is typically represented in clinical trials. The average patient in our data set is different from the average patient in a clinical trial. If someone wants to tailor an intervention to characteristics that are representative of their patient population, they may be more likely to lean on real-world findings. Patients may differ in disease stage, prognosis, age, comorbidities, and other characteristics. Clinicians may therefore look more closely at real-world data, including studies like ours and others in the literature, to make more informed decisions than trial evidence alone can provide.
Are there any additional key takeaways you'd like to highlight from the study?
Dr Mudumba: To our knowledge, this is the largest observational or real-world study in the US to date on this topic. We were able to accrue a large sample from a national claims data set, so we're confident that patients were not only prescribed these agents but also filled them. At the same time, the sample sizes for 2 of the most interesting comparisons—brigatinib and lorlatinib—are still too small to make definitive claims. In the future, if someone can run a similar study with a larger sample for those treatment arms, we may be able to generate evidence that could more directly shape guidelines. This clinical question could become much easier to answer if researchers use a later data cut and continue following patients over the next several years. Hopefully, within the next year or 2, we will have greater differentiation among these agents, which would be very helpful to clinicians.
