Seven Years Strong: Updated CROWN Data Showcase Lorlatinib's Durability in ALK+ NSCLC at ASCO 2026

At the 2026 ASCO Annual Meeting, results from the 7-year update of the phase 3 CROWN study (NCT03036488) were presented.¹

At a median follow-up of 83.0 months (95% CI, 81.2-86.3) for lorlatinib (Lorbrena; n = 149) and 77.2 months (95% CI, 36.8-not evaluable) for crizotinib (Xalkori; n = 147), the median PFS was still not reached (NR; 95% CI, 68.5 months-NR) vs 9.1 months (95% CI, 7.4-10.9), respectively (HR, 0.19; 95% CI, 0.13-0.26), in patients with advanced ALK-positive non–small cell lung cancer (NSCLC). The 7-year PFS rates in the respective arms were 55% vs 3%. In total, 7 new PFS events were reported between 5 and 7 years in the lorlatinib arm; 4 were progression events, and 3 were deaths (all of which were deemed not related to treatment).

No new intracranial (IC) progression events occurred after the first 30 months on lorlatinib. The median times to IC progression was NR (95% CI, NR-NR) and 16.4 months (95% CI, 12.7-21.9), respectively (HR, 0.06; 95% CI, 0.03-0.12). The 7-year IC PFS rates were 92% vs 16%, respectively.

Among patients with baseline brain metastases, the time to IC progression was NR (95% CI, NR-NR) in the lorlatinib arm (n = 35) vs 7.2 months (95% CI, 3.7-11.0) in the control arm (n = 38; HR, 0.03; 95% CI, 0.01-1.13). Among patients without baseline brain metastases, the time to IC progression was NR (95% CI, NR-NR) in the lorlatinib arm (n = 114) vs 23.9 months (95% CI, 16.4-30.8) in the control arm (n = 109; HR, 0.04; 95% CI, 0.02-0.12).

Long-term efficacy outcomes with lorlatinib were similar between patients who did and did not undergo dose reductions within 26 weeks. Among patients with dose reductions, the median PFS (n = 23) was NR (95% CI, 79.8 months-NR), and the median time to IC progression was NR (95% CI, NR-NR). Among patients without dose reductions, the median PFS (n = 98) was NR (95% CI, 81.9%-NR), and the median time to IC progression (n = 99) was NR (95% CI, NR-NR). Notably, the PFS and time to intracranial progression outcomes were also consistent across lorlatinib dose levels (100 mg, 75 mg, or 50 mg).

The PFS benefit with lorlatinib was consistent across all prespecified subgroups, including patients with brain metastases (HR, 0.08; 95% CI, 0.04-0.19) or without brain metastases (HR, 0.23; 95% CI, 0.16-0.34), as well as in Asian (HR, 0.24; 95% CI, 0.15-0.39) and non-Asian (HR, 0.18; 95% CI, 0.11-0.28) populations.

Tony Mok, BMSc, MD, FRCPC, FHKCP, FHKAM, FRCP, sat down with OncLive® at ASCO 2026 to talk through what these findings mean for the ALK-positive NSCLC treatment paradigm.

Mok is associate dean of Translation and Entrepreneurship, chairman of the Department of Clinical Oncology, and the Li Shu Fan Professor of Clinical Oncology at The Chinese University of Hong Kong.

“I can tell my patients that if they are progression free by the second year, they will have approximately a 79% chance that they may remain progression free at the end of the seventh year, which is an important message for patients,” Mok emphasized.

The presentation follows a 5-year post hoc analysis published in the Journal of Clinical Oncology that showed median progression-free survival (PFS) had not been reached with lorlatinib vs a median of 9.1 months (95% CI, 7.4-10.9) with crizotinib, corresponding to an HR of 0.19 (95% CI, 0.13-0.27) in patients with advanced ALK-positive NSCLC.²

Regarding safety, the safety profile of lorlatinib was consistent with that seen in prior analyses, and the investigators observed no increases in the frequency of grade 3/4 adverse effects since the 5-year analysis. In total, 34% of patients in the lorlatinib arm required dose reductions, with a median time to dose reduction of 25 weeks. Additionally, 5% of patients experienced treatment-related discontinuations, all of which occurred within the first 26 months of treatment. AEs of special interest included edema (lorlatinib arm, 58%; crizotinib arm, 43%), hypertriglyceridemia (71%; 6%), hypercholesterolemia (73%, 4%), peripheral neuropathy (46%; 16%), weight gain (45%; 13%), cognitive effects (30%; 7%), mood effects (21%; 7%), psychotic effects (5%; 1%), and speech effects (6%; 0%).

Notably, no emergent ALK resistance mutations were seen in the circulating tumor DNA (ctDNA) samples collected at the end of treatment with lorlatinib. New putative resistance mechanisms included those in FLT1/VEGFR1, XRCC2, and HDAC6. Furthermore, patients who experienced early progression (n = 22) had a higher median number of altered genes (10 vs 6) and a higher median blood-based tumor mutational burden (7.7 vs 5.1) compared with patients with longer-term responses (n = 30). In total, 50% of samples from patients who experienced early progression harbored TP53 mutations vs 17% of those from patients who experienced longer-term responses.

How was the CROWN trial designed?

CROWN is an ongoing, international, open-label, randomized, phase 3 trial conducted across 104 centers in 23 countries that evaluates lorlatinib vs crizotinib in patients with previously untreated, advanced, ALK-positive NSCLC.

A total of 296 patients were randomly assigned 1:1 to receive lorlatinib 100 mg once daily (n = 149) or crizotinib 250 mg twice daily (n = 147) in 28-day cycles. Eligible patients had stage IIIB/IV ALK-positive NSCLC without prior systemic treatment for metastatic disease, an ECOG performance status of 2 or lower, and at least 1 extracranial measurable target lesion. Patients with asymptomatic, treated, or untreated central nervous system metastases were eligible, and no crossover between arms was permitted. Patients were stratified by the presence of brain metastases (yes vs no) and ethnicity (Asian vs non-Asian).

The primary end point was PFS by blinded independent central review (BICR) per RECIST 1.1 criteria; the key secondary end point was overall survival (OS), to be assessed at a protocol-specified second interim analysis after at least 139 deaths.

What CROWN findings have previously been reported?

At the initial interim analysis, lorlatinib produced a 72% reduction in the risk of progression or death vs crizotinib per BICR assessment (HR, 0.28; 95% CI, 0.19-0.41; P <.0001), with median PFS not reached in the lorlatinib arm.³

These data supported the March 2021 FDA approval of lorlatinib for adult patients with metastatic NSCLC whose tumors are ALK-positive as detected by an FDA-approved test, expanding the agent's indication and converting its November 2018 accelerated approval to a full approval.⁴ At the 3-year post hoc analysis, median PFS by BICR remained not reached in the lorlatinib arm with continued superior benefit over crizotinib.²

The 5-year post hoc analysis,⁵ presented at the 2024 ASCO Annual Meeting and simultaneously published in the Journal of Clinical Oncology, demonstrated that median PFS had still not been reached with lorlatinib at a median follow-up of 60.2 months (95% CI, 57.4-61.6), vs 9.1 months (95% CI, 7.4-10.9) with crizotinib (HR, 0.19; 95% CI, 0.13-0.27).⁶ The 5-year PFS rates were 60% (95% CI, 51-68) vs 8% (95% CI, 3-14), respectively. Among patients with baseline brain metastases (n = 35 lorlatinib; n = 38 crizotinib), lorlatinib led to a median PFS of not reached (95% CI, 32.9-NR) vs 6.0 months (95% CI, 3.7-7.6) with crizotinib (HR, 0.08; 95% CI, 0.04-0.19); 5-year PFS was 53% with lorlatinib, and no patients in the crizotinib arm remained progression free at 2 years. At 5 years, 50% of patients in the lorlatinib arm were still receiving treatment, compared with 5% in the crizotinib arm.

In a recent OncLive Peer Exchange program, panelists discussed how lorlatinib has become the new standard of care for ALK-positive patients based on CROWN trial data showing unprecedented 5-year PFS.⁷

In a Bridging the Gaps video series, Benjamin P. Levy, MD, and Misty D. Shields, MD, further explained how the 5-year follow-up data from the trial support lorlatinib as a frontline treatment for ALK-positive NSCLC with brain metastasis.⁸

In an exclusive interview, D. Ross Camidge, MD, PhD, of the University of Colorado Cancer Center – Anschutz Medical Campus, unpacked ways that ALK-positive NSCLC management has changed based on 5-year follow-up data with lorlatinib in the CROWN trial.⁹

What is the significance of the CROWN trial for the ALK+ NSCLC space?

“At the 2024 ASCO Annual Meeting, we saw the 5-year follow-up data from the CROWN trial showing unprecedented PFS benefit, which became practice changing for many of our frontline [patients with] ALK-positive disease,” Eric K. Singhi, MD, said in an exclusive conference preview with OncLive.¹⁰ [At this year’s meeting] we will hear about the 7-year follow-up data, which will continue to provide reasoning for frontline use of lorlatinib [Lorbrena].”

Tony SK Mok, MD, FRCPC, FASCO, of Chinese University of Hong Kong, in Hong Kong, China will present the full results as part of a highly anticipated oral abstract session on May 29, 2026.

References

1. Mok TS, Solomon BJ, Felip E, et al. Lorlatinib vs crizotinib as first-line treatment for advanced ALK+ non-small cell lung cancer: 7-year update from the phase 3 CROWN study. J Clin Oncol. 2026;44(suppl 16):8502. doi:10.1200/JCO.2026.44.16_suppl.8502
2. Solomon BJ, Liu G, Felip E, et al. Lorlatinib versus crizotinib in patients with advanced ALK-positive non-small cell lung cancer: 5-year outcomes from the phase III CROWN study. J Clin Oncol. 2024;42(29):3400-3409. doi:10.1200/JCO.24.00581
3. Shaw AT, Bauer TM, de Marinis F, et al. First-line lorlatinib or crizotinib in advanced ALK-positive lung cancer. N Engl J Med. 2020;383(9):2018-2029. doi:10.1056/NEJMoa2027187
4. FDA approves lorlatinib for metastatic ALK-positive NSCLC. News release. FDA. March 3, 2021. Accessed May 21, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-lorlatinib-metastatic-alk-positive-nsclc
5. Dagogo-Jack I. Lorlatinib vs crizotinib in treatment-naive patients with advanced ALK+ non-small cell lung cancer: 5-year progression-free survival and safety from the CROWN study. OncLive.com. June 17, 2024. Accessed May 21, 2026. https://www.onclive.com/view/lorlatinib-vs-crizotinib-in-treatment-naive-patients-with-advanced-alk-non-small-cell-lung-cancer-5-year-progression-free-survival-and-safety-from-the-crown-study
6. Solomon BJ, Liu G, Felip E, et al. Lorlatinib versus crizotinib in patients with advanced ALK-positive non–small cell lung cancer: 5-year outcomes from the phase III CROWN study. J Clin Oncol. 2024;42(29):3400-3409. doi:10.1200/JCO.24.00581
7. Sabari JK, Bestvina C, Husain H, Rotow J. Decoding efficacy and safety outcomes among second- and third-generation ALK inhibitors. OncLive.com. July 9, 2025. Accessed May 21, 2026. https://www.onclive.com/view/decoding-efficacy-and-safety-outcomes-among-second-and-third-generation-alk-inhibitors
8. Levy BP, Shields MD. Latest advances in management of advanced NSCLC with ALK or ROS1 mutations. OncLive.com. March 21, 2025. Accessed May 21, 2026. https://www.onclive.com/view/latest-advances-in-management-of-advanced-nsclc-with-alk-or-ros1-mutations
9. Wahner A. Strategic and safe lorlatinib use is key to optimal ALK+ NSCLC management: Q&A with D. Ross Camidge, MD, PhD. OncLive.com. February 21, 2025. Accessed May 21, 2026. https://www.onclive.com/view/strategic-and-safe-lorlatinib-use-is-key-to-optimal-alk-nsclc-management
10. Seymour C. Track the lung cancer abstracts that are gaining attention at ASCO 2026. May 7, 2026. Accessed May 21, 2026. https://www.onclive.com/view/track-the-lung-cancer-abstracts-that-are-gaining-attention-at-asco-2026