Long-term outcomes with lorlatinib vs. crizotinib in ALK-positive NSCLC: Insights from the CROWN study: Written recap

In this Managed Healthcare Executive “Between the Lines” video program, Christine M. Lovly, M.D., Ph.D., and Alice Shaw, M.D., Ph.D., discussed seven-year follow-up results from the phase 3 CROWN study comparing lorlatinib with crizotinib as first-line treatment for advanced ALK-positive non-small cell lung cancer (NSCLC). The two oncologists covered the epidemiology of ALK-positive disease, current approaches to biomarker testing, the CROWN trial’s long-term efficacy and safety findings, and practical strategies for managing lorlatinib’s side effects over years of continuous treatment. Lovly is a professor of medical oncology and division chief of thoracic medical oncology at City of Hope Cancer Center Duarte in California. Shaw is chair of the Department of Medical Oncology and chief of strategic partnerships at Dana-Farber Cancer Institute in Boston.

A biomarker with an outsized impact

Lovly opened the discussion by asking Shaw to frame the epidemiology and prognosis of ALK-positive NSCLC. Shaw explained that ALK rearrangements were first identified in lung cancer in 2007 and that the biomarker accounts for approximately 4% to 5% of NSCLC cases, a relatively small fraction, she noted, but one that still translates into a large absolute number of patients worldwide, making it an important subset for treatment development.

Prognosis for these patients has changed dramatically over the past two decades, Shaw said. Before targeted therapies existed, patients with ALK-positive disease fared no better than other patients with advanced lung cancer. The arrival of successive generations of ALK inhibitors has dramatically improved outcomes.

Lovly and Shaw discussed the sometimes confusing terminology surrounding ALK. Lovly explained that “ALK rearranged,” “ALK fusion” and even “ALK mutation” are used interchangeably, which can confuse patients trying to understand their diagnosis. Both speakers agreed to standardize on “ALK positive” for clarity, noting that all of these terms refer to the same underlying rearrangement involving chromosome 2, where the ALK gene is located. Lovly added that the ALK kinase itself was first discovered in a translocation associated with anaplastic large cell lymphoma, a reminder that the same biomarker can surface across very different tumor types.

Testing before treatment

Shaw walked through the current landscape of ALK testing, emphasizing that comprehensive molecular profiling should be performed on all patients with NSCLC. Liquid biopsies, which find and analyze circulating tumor DNA, offer a fast, noninvasive way to screen for actionable alterations, including ALK rearrangements. However, Shaw cautioned that liquid biopsies have sensitivity limitations, and a negative result does not rule out an ALK rearrangement. Tumor tissue testing — using next-generation sequencing of DNA or RNA, or ALK immunohistochemistry — remains necessary to confirm biomarker status.

Lovly reinforced that point for the audience, stressing that effective ALK-targeted therapy cannot be delivered without reliable testing and that molecular pathologists and testing company partners can help clinicians understand the limitations of any given assay. The pair noted that this conversation would focus on advanced or metastatic disease, acknowledging that ALK-targeted therapy is also approved in early-stage lung cancer, a topic outside the scope of this program.

Shaw also walked through the treatment choices once a patient’s stage 4, ALK-positive status is confirmed. Because the cancer has typically spread beyond the lung — often to the liver, bone or brain — first-line treatment requires a systemic therapy that can reach the whole body, whether given orally or intravenously. ALK-targeted therapy has long since replaced chemotherapy as the preferred first-line approach in this setting.

“We know now, after many years, that ALK-targeted therapy is the most effective first-line therapy we should give,” Shaw said. “We’ve already shown that it is much more effective than standard therapy, so we would never consider chemotherapy in the first setting.”

The complexity, Shaw said, is that the second-generation ALK inhibitors alectinib, brigatinib and ensartinib — and the third-generation inhibitor lorlatinib are all listed as preferred first-line therapies under National Comprehensive Cancer Network (NCCN) guidelines. That, she said, is precisely why the CROWN data matter so much to prescribers trying to choose among them.

‘Being able to exhale’

A seven-year update of the CROWN study was presented at the 2026 American Society of Clinical Oncology (ASCO) Annual Meeting. Researchers randomly assigned 296 treatment-naive patients with stage 4, ALK-positive NSCLC to be treated with either lorlatinib or crizotinib, an earlier-generation option. As of the October 31, 2025, data cutoff, 44% of patients remained on lorlatinib after seven years versus just 3% still on crizotinib, Lovly noted. The median follow-up was 83 months for the lorlatinib arm and 77.2 months for the crizotinib arm.

The median progression-free survival (PFS) for lorlatinib has still not been reached at seven years, compared with 9.1 months for crizotinib, a hazard ratio of 0.19. The median time to intracranial progression has not yet been reached with lorlatinib, versus 16.4 months with crizotinib. Grade 3 or 4 adverse events occurred in 77% of patients on lorlatinib and 57% on crizotinib, though permanent discontinuation rates were similar between arms, at 5% and 6%, respectively.

Shaw put the results in historical context, noting that before targeted therapies, median survival for advanced lung cancer was 12 months or less. “I don’t know that I’ve ever seen that,” she said of the seven-year follow-up, referencing a comment from lead investigator Tony Mok, M.D., at ASCO. “I think this is quite remarkable, and it does highlight the incredibly durable activity of this targeted therapy.”

Lovly asked Shaw which end point matters most when she is explaining these results to patients. Shaw mentioned PFS because it tells patients roughly how long their cancer is likely to remain controlled; response rate because shrinking tumors usually track with symptom relief; intracranial activity because up to 30% of ALK-positive patients already have brain metastases at diagnosis; and long-term safety.

Most of the patients in the lorlatinib arm of the study whose cancer progressed did so within the first two years, Shaw noted. Patients who reached the two-year mark without progression had an approximately 79% probability of remaining progression-free at seven years. Shaw said being able to tell the patients who made it through the first two years that they have almost an 80% chance of their cancer not progressing “completely changes how patients are perceiving their disease and living their life.” Lovly said for patients in that group, “it’s almost a moment of being able to exhale in a way that they haven’t been able to before.”

Shaw said that, as far as overall survival is concerned, the data set remains immature, but the PFS findings are reason to be optimistic that it will exceed the overall survival findings for alectinib. “I would say we’re incredibly hopeful that overall survival is going to look spectacular,” she said.

Lovly sounded a cautionary note that, notwithstanding the positive CROWN trial results, not every patient benefits and that continued advocacy for better therapies remains necessary.

Lovly and Shaw also discussed how to identify patients in the group whose cancers progress during the first two years of lorlatinib treatment. Shaw mentioned research she has been involved in that used findings from liquid biopsies to compare patients who progressed within the first year against those who were still responding at seven years. “So really, the extremes of early progression versus durable response,” she said. Patients who progressed early tended to have more genetic alterations at baseline, a higher tumor mutation burden and more frequent mutations in the tumor suppressor gene p53. Shaw noted that the analysis is preliminary and the sample sizes are small, but it may point to a future in which a biomarker could identify high-risk patients for intensified treatment from the start.

Living with lorlatinib long-term

Because patients may take lorlatinib for years, Shaw spent considerable time detailing its side effect profile, which differs from other ALK inhibitors. The most common issue is elevated cholesterol and triglycerides, which often occur within two weeks of starting treatment and typically requires a statin or other lipid-lowering therapy. Other effects include fluid retention, weight gain driven by increased appetite and a constellation of neurocognitive and mood symptoms, including brain fog and mood intensification.

All of these effects are reversible and dose-dependent, Shaw said, which makes dose reduction a central management tool. Although the standard starting dose tested in the CROWN study was 100 milligrams once daily, Shaw described her own practice of starting many patients, particularly those who are older or frail, at 75 milligrams. “I have just used this drug for so many years now — for over 12 years — and I find 100 milligrams to be a very difficult … dose to tolerate,” she said. She noted that prescribing lorlatinib as four 25-milligram tablets rather than a single 100-milligram tablet allows for faster, easier dose adjustments without a new prescription. Frequent early monitoring, including labs and side effect checks initially every two weeks, followed by gradual spacing to every six months for long-term patients, helps catch problems before they affect quality of life, she explained.

Weight gain and fluid retention tend to persist or worsen gradually over years of treatment, Shaw said, and managing them requires an active, team-based approach: dietary counseling, an exercise regimen combining aerobic activity and strength training, and referral to a nutritionist when needed. She said patients and clinicians sometimes ask about glucagon-like peptide 1 (GLP-1) drugs to offset lorlatinib-related weight gain. Although there have been some reports, more robust evidence is needed before GLP-1s are routinely recommended. Shaw said counseling before a patient even starts the drug, along with written materials and biweekly visits for the first several months of treatment, can help patients and their families anticipate and cope with the side effects.

What it means for practice

Both oncologists said the seven-year CROWN data should influence how first-line therapy is chosen in community and academic settings alike. Despite the NCCN guidelines that list alectinib, brigatinib and ensartinib, along with lorlatinib, as preferred first-line options, Shaw argued that the phase 3 CROWN results set lorlatinib apart. “You have to have a real justification for not offering lorlatinib,” she said, citing scenarios such as an older, frail patient with significant comorbidities or a patient with baseline psychiatric illness as reasonable exceptions.

Shaw's top takeaways were an unprecedented PFS benefit unmatched by any other lung cancer therapy; remarkable central nervous system activity, with 92% of patients remaining free of intracranial progression at the seven-year mark; and a manageable, if persistent, safety profile that requires ongoing counseling and monitoring. Overall survival data remain immature, though both speakers said they are hopeful the results will be equally strong, given the extraordinary PFS benefit.

Shaw added that lorlatinib’s PFS advantage over second-generation inhibitors — a median of two to three years for alectinib, brigatinib and ensartinib versus a median not yet reached beyond seven years for lorlatinib — was not measured in a head-to-head trial. Even so, she said the separation between the trials is large enough to be clinically meaningful, and it is one reason she considers lorlatinib the preferred first-line option for most newly diagnosed ALK-positive patients, rather than a single choice among several equally weighted alternatives.

Lovly closed the program by reiterating that these outcomes are only possible with universal biomarker testing, as ALK-targeted therapies cannot be delivered without first identifying the mutation. She also pointed viewers to ALK Positive, a patient advocacy group that supports patients and families and helps fund research, as a resource.