Do Clinical Trial Results Hold Up in the Real World? A New Study on ALK+ Lung Cancer Says Yes—Mostly

Clinical trials are designed to answer a narrow question under tightly controlled conditions: Does this drug work better than that drug in this specific group of patients? What they're not built to answer is what happens when that same drug reaches everyone else: the patients who are older, sicker, or managing more than one disease at once and who would never have qualified for the trial in the first place.

That gap is what Jorge J. Nieva, MD, professor of clinical medicine at the Keck School of Medicine of USC, and colleagues set out to address in a new real-world analysis of targeted therapies for ALK-positive non–small cell lung cancer (NSCLC), published in the journal Lung Cancer.¹

"We were really trying to get at understanding whether or not the findings from clinical trials are applicable to real-world populations and just how applicable they are," Nieva said in an interview with Targeted Oncology. "We wanted to be sure that the benefits seen with treatment with newer-generation agents were something that was applicable broadly and applicable to patients who wouldn't normally meet clinical trial inclusion criteria."

What the Data Showed

ALK-positive lung cancer, in which the ALK gene fuses abnormally with another gene, accounts for a small slice of lung cancer diagnoses overall, but it produces a faulty protein that drives tumor growth and is treatable with a class of targeted drugs called ALK tyrosine kinase inhibitors (TKIs). Several of these drugs are now approved for first-line use, leaving physicians and patients to weigh which one to start with—a decision largely informed by trial data that may not reflect their actual situation.

Using insurance claims data drawn from 940 patients treated for ALK-positive lung cancer between 2016 and 2024, Nieva and his colleagues compared outcomes across 5 TKIs: crizotinib (Xalkori), alectinib (Alecensa), brigatinib (Alunbrig), lorlatinib (Lorbrena), and ceritinib (Zykadia). The results pointed in a clear direction. "We found that there was improvement in survival for patients treated with alectinib compared with those treated with crizotinib," Nieva said. "We have small groups of patients treated with brigatinib and lorlatinib, but I think the numbers were too small to make meaningful comparisons."

In the full analysis, patients on alectinib had a median overall survival of 46.5 months and stayed on treatment for a median of 33.5 months, outperforming crizotinib, the original first-generation ALK inhibitor, on both measures.

Lining Up with the Trial Data

For Nieva, one of the most reassuring parts of the analysis was how closely it tracked with the existing clinical trial evidence, particularly the landmark ALEX trial (NCT02075840), which established alectinib's superiority over crizotinib in a controlled setting.² "I think they actually lined up very well," he says of his team's real-world findings. "Which were very similar to what one would have expected to see based on the results of the ALEX trial, so I was very happy to see that the benefits seem to hold up."

That confirmation matters for a reason that goes beyond academic interest, Nieva said, especially as the patent landscape around these drugs begins to shift. "I think this is increasingly important as we begin to see availability of generic forms of some of the older drugs," he said. "I think a lot of people might be tempted to say, well, couldn't we just treat the patient with the generic first-generation agent and save a lot of money? And I think what this analysis showed us was that in a real-world population, that would probably be inappropriate to do."

Who Gets Left Out of Trials—and Why It Matters

Much of the value of a real-world dataset comes from who it includes that a clinical trial wouldn't. Asked what typically excludes patients from the kind of trials that produced drugs like alectinib in the first place, Nieva points to a familiar list. "Performance status is probably the biggest exclusion criterion," he said. “The presence of secondary malignancies and renal and hepatic dysfunction oftentimes would be exclusion criteria as well."

But formal exclusion criteria are only part of the story. Access itself is often the bigger barrier. "I think there are just some patients who don't want to participate in clinical trials for whatever reason, and I think the most common reason is that they're not people who get their care at centers that offer clinical trials," Nieva said. That access gap is precisely why studies like his carry weight, he said: "We do want to be sure that community populations who are not clinical trial participants most of the time receive similar benefits to those generally healthier, wealthier, more mobile patients who oftentimes receive their care at academic medical centers, where these clinical trials are usually available."

Implications for Practice

For physicians weighing which ALK inhibitor to start a patient on, Nieva sees these findings as reinforcing a fairly direct message: don't wait to use the better drug. "These practice data support the continued use of more advanced ALK inhibitors in the treatment of patients," he said. The pattern, in his view, extends beyond this comparison. "These findings that we're getting from clinical trials, which are really showing that newer-generation agents are a meaningful improvement over earlier-generation agents—we really have to think broadly about what benefits newer agents have over older agents, and that they really should be adopted fairly early on."

That principle will only become more relevant as the pipeline of ALK inhibitors continues to expand, Nieva noted. "We're seeing now third- and maybe even fourth-generation ALK inhibitors coming to market, and these agents are really showing tremendous benefits to patient populations as well. So, we'll really need to think about adopting new agents as they are available in order to make sure that our patients really have the longest survival time possible with the least amount of toxicity."

What's Still Unanswered

The study's biggest limitation, in Nieva's view, was sample size for the newest drugs in the comparison—particularly lorlatinib, a third-generation ALK inhibitor that has shown striking efficacy results in other contexts but comes with its own complications. "I would have liked this research to have a larger population of lorlatinib-treated patients, which we didn't have in the study population that our database gave us access to," he says. "I think that'll be an important thing to look at in the future, because we're seeing really fantastic results from the CROWN [NCT03052608] data, from the standpoint of survival, but we have to temper that with the significant neurocognitive toxicity that that drug also has."

Understanding how that tradeoff plays out outside of a trial setting, where dose adjustments are common and patients vary widely, is the next open question for Nieva. "Understanding what that means in a real-world population, I think, is going to be important," he said. "Understanding the need for dose reductions for agents that may have greater toxicity is going to be valuable, and understanding whether or not those dose reductions have a meaningful impact on survival in a real-world population is a question I still have."

He hopes to revisit the question down the line. "I look forward to being able to repeat this study in the future with a new database of community-treated patients, to really understand the benefits of newer agents relative to the second-generation ALK inhibitors."

REFERENCES

1. Mudumba R, Liu X, Jin S, et al. Comparative effectiveness of first-line targeted therapies in ALK-positive non-small cell lung cancer: real-world evidence of tyrosine kinase inhibitors. Lung Cancer. 2026 Jul;217:109451. doi: 10.1016/j.lungcan.2026.109451. Epub 2026 May 10. PMID: 42134157.

2. Peters S, Camidge DR, Shaw AT, et al. Alectinib versus Crizotinib in Untreated ALK-Positive Non-Small-Cell Lung Cancer. N Engl J Med. 2017 Aug 31;377(9):829-838. doi: 10.1056/NEJMoa1704795. Epub 2017 Jun 6. PMID: 28586279.