“7-year Lorviqua data reshape trt strategy for ALK-positive lung cancer”

Professor Byoung Chul Cho of the Division of Medical Oncology at Yonsei Cancer Center

Median progression-free survival (PFS) has still not been reached…55% of patients maintained progression-free at 84 months

Long-term efficacy in suppressing brain metastasis has been confirmed…strengthening the evidence for potential use as a first-line treatment

"The clinical data from the CROWN trial for Lorviqua demonstrated significant differences in progression-free survival, which is incomparable to existing ALK-targeted therapies. These results indicate that rather than debating the optimal sequence of treatments, clinicians should select the most effective therapeutic agent from the very beginning."

Professor Byoung Chul Cho of the Division of Medical Oncology at Yonsei Cancer Center

​During a recent meeting with DailyPharm, Professor Byoung Chul Cho of the Division of Medical Oncology at Yonsei Cancer Center shared his assessment of the 7-year long-term follow-up results from the global Phase 3 CROWN study of 'Lorviqua (lorlatinib).’

​Professor Cho assessed that with Lorviqua demonstrating durable long-term disease control and robust intracranial efficacy, the treatment paradigm for ALK-positive non-small cell lung cancer (NSCLC) is rapidly shifting from a 'sequential therapy' model to a focus on 'optimal first-line treatment'.

​ALK-positive NSCLC is a rare subtype accounting for approximately 3% to 5% of all NSCLC cases. It frequently presents in relatively younger patient populations and is heavily characterized by a high incidence of brain metastasis at initial diagnosis.

Approximately 20% to 40% of these patients present with brain metastases at the time of initial diagnosis, and central nervous system (CNS) progression occurs frequently throughout the course of treatment, making it a representative lung cancer subtype that threatens both patient survival and quality of life.

Consequently, in recent years, key endpoints in ALK-positive NSCLC treatment have shifted from objective response rate (ORR), which measures tumor shrinkage, toward how long a therapy can delay disease progression and protect the brain.

Lorviqua, a third-generation ALK inhibitor specifically designed to cross the blood-brain barrier (BBB) effectively, is recognized as a primary driver of this therapeutic paradigm shift.  

​According to the 7-year follow-up data from the global Phase 3 CROWN study, the median progression-free survival (PFS) in the Lorviqua cohort has still not been reached, and 55% of patients maintained progression-free at 84 months of treatment.  

Furthermore, Lorviqua demonstrated an 81% reduction in the risk of disease progression or death compared to the first-generation ALK inhibitor 'Xalkori (crizotinib).' Approximately 79% of patients who achieved stable disease control during the first two years of treatment remained progression-free through the 7-year mark.  

​The long-term effect on suppressing brain metastases was also sustained over extended periods. At the 7-year mark, the proportion of patients who remained free of intracranial disease progression was 92% in the Lorviqua cohort and 16% in the crizotinib cohort. Additionally, 96% of patients without baseline brain metastases remained free of new intracranial lesions. Even among patients with preexisting brain metastases, 83% continued their treatment without experiencing intracranial disease progression.

​Major clinical guidelines, including the National Comprehensive Cancer Network (NCCN), the American Society of Clinical Oncology (ASCO), and the European Society for Medical Oncology (ESMO), recommend the third-generation inhibitor Lorviqua as a first-line treatment option for ALK-positive NSCLC.

​In South Korea, the clinical utility of Lorviqua has expanded significantly since national health insurance reimbursement was granted for the first-line treatment of ALK-positive metastatic NSCLC last year.

​Professor Cho evaluated that “These 7-year long-term follow-up results do not merely confirm survival extension; rather, they provide robust evidence supporting the clinical importance of a strategy that maximally suppresses disease progression and brain metastases at the earliest therapeutic intervention.”

Professor Cho explained, “As long-term disease control becomes achievable for a subset of patients, the ultimate goal of ALK-positive NSCLC management is expanding from short-term tumor response to chronic, long-term disease management.

Q. What was notable about the 7-year follow-up results from the CROWN study?

The therapeutic efficacy demonstrated in this dataset is so significant that it is difficult to draw comparisons to existing ALK-targeted therapies. Even at the 7-year follow-up, the median PFS in the Lorviqua cohort has not yet been reached. In contrast, the median PFS in the control arm hovered around 9.1 months, representing an exceptionally wide clinical gap. The hazard ratio is remarkably low at 0.19.  

​In EGFR-mutant lung cancer, the efficacy gap between first- and second-generation agents, or between first- and third-generation agents, was relatively narrow, allowing ongoing debate regarding treatment sequencing and cost-effectiveness. In contrast, the CROWN data show such a profound differences in therapeutic efficacy that it renders those sequencing debates virtually obsolete.

The fact that 55% of patients in the Lorviqua cohort remained progression-free at 84 months is also a meaningful clinical outcome. While nearly all patients in the control group experienced disease progression before this landmark, more than half of the patients receiving frontline Lorviqua remained entirely free of progression.  

Data demonstrating this magnitude of therapeutic benefit are exceptionally rare in clinical oncology, and I believe these results will fundamentally reshape paradigms in real-world clinical practice.

Q. How do you interpret the plateau observed in the PFS curve after 2-years in the 7-year follow-up data?

The most intriguing aspect of this dataset is the 2-year landmark analysis. Irrespective of the therapeutic agent deployed, there always exists a cohort of high-risk patients who experience early disease progression, and approximately 30% of patients on Lorviqua progressed within the first two years. However, after crossing the 2-year threshold, the rate of disease progression declined sharply, with only about 15% of patients experiencing further progression through the 7-year mark. This resulted in the Kaplan-Meier curve forming a distinct plateau.

​With typical targeted therapeutics, the PFS curve continues to decline steadily over time. In this study, however, the majority of patients who surpassed the initial phase maintained stable disease control for an extended period. This pattern is highly unusual for a tyrosine kinase inhibitor and closely resembles the "tail plateau" or tail effect commonly observed with cancer immunotherapies. However, unlike immunotherapies, Lorviqua requires continuous, ongoing administration to sustain this effect.

Currently, we cannot fully explain which specific patient types are predisposed to this long-term durable response, beyond the established clinical understanding that patients with concurrent TP53 mutations or other co-mutations face a heightened risk of early progression. ​The fact that long-term disease control is maintained among patients who survive beyond 2 years represents the most significant clinical takeaway from this 7-year dataset.

Q. How should the objective response rate (ORR) and complete response (CR) data be interpreted in real-world clinical practice?

The ORR is not a metric that reveals stark contrasts among first-, second-, and third-generation ALK inhibitors. Most ALK TKIs elicit a similar initial tumor response, whereas Lorviqua's true therapeutic strength lies in its ability to sustain that response over extended timelines. Therefore, rather than focusing heavily on ORR or CR, clinicians analyzing this dataset should prioritize median PFS, long-term PFS rates, and durable long-term disease control.  

Notably, the CROWN study demonstrated consistent therapeutic benefits across all prespecified patient subgroups. The regimen showed particularly outstanding efficacy in the high-risk cohort with baseline brain metastases, yielding a hazard ratio of 0.08 in patients with baseline brain lesions and 0.23 in those without. Typically, patients presenting with brain metastases experience poorer treatment outcomes, but these results demonstrate an inverse trend, which underscores the profound clinical value of the drug.

Consequently, the core significance of these results lies not in simple, short-term tumor shrinkage, but in the therapy's capability to sustain clinical responses over the long term while delivering consistent efficacy even in patient cohorts with historically poor prognoses.

Q. How do you evaluate the long-term brain metastases suppression efficacy and long-term follow up results?

Brain metastasis is exceptionally common in ALK-positive NSCLC, with approximately 40% of patients presenting with intracranial lesions at initial diagnosis, and a high proportion of patients developing new brain metastases while on first-generation ALK inhibitors. Consequently, protecting the brain stands as one of our most critical therapeutic priorities.

The CROWN study is highly meaningful as it is the first trial to conduct regular, protocol-specified brain MRIs for all enrolled patients, regardless of whether they had baseline brain metastases. Patients underwent brain MRIs every 8 weeks for the first 5 years and every 16 weeks thereafter. This rigorous protocol allowed for a highly reliable and systematic assessment of intracranial PFS and intracranial ORR.

The most notable finding from this 7-year analysis is the durability of the brain-protective effect. Among patients without baseline brain metastases, approximately 96% remained free of intracranial progression at the 2-year mark, and this rate remained virtually unchanged at 96% at the 7-year mark. This indicates that almost no patients developed new brain metastases during the subsequent 5 years of follow-up. Even among those with baseline brain metastases, very few experienced further intracranial progression after the 2-year mark, demonstrating that Lorviqua is an exceptionalltherapeutic for long-term CNS protection.

Q. What is your clinical assessment of Lorviqua’s safety profile?

The adverse events associated with Lorviqua include peripheral edema, hyperlipidemia, and cognitive effects. Cognitive side effects can present as mood swings or depressive symptoms, and psychiatric adverse events have been reported in rare instances. However, in real-world clinical practice, severe psychiatric toxicities are exceptionally rare, and the vast majority of cases are Grade 1 or 2 events that are highly manageable.

Hyperlipidemia is primarily detected through routine laboratory monitoring and is easily managed using standard lipid-lowering therapies. In daily practice, most patients manage this successfully by obtaining standard lipid prescriptions from local clinics, with very few experiencing severe clinical complications.

Crucially, the 7-year dataset confirms that dose reduction due to treatment-induced adverse events does not result in a clinically significant loss of therapeutic efficacy. Therefore, even when Grade 3 or higher toxicities arise, clinicians can confidently adjust the dosage to maintain long-term treatment continuity, confirming that Lorviqua is highly tolerable over extended, multi-year timelines.

Q. Following the approval of first-line reimbursement for Lorviqua, how has clinical decision-making evolved, and does the concept of sequential therapy across ALK TKIs still hold relevance?

Since the implementation of first-line reimbursement, Lorviqua became our primary frontline option, dramatically reducing the historical instances in which it was restricted to a select few due to cost or access barriers. With the therapy now broadly accessible, the clinical decision-making framework has evolved from "selecting among available drugs" to identifying which agent will deliver the most powerful, upfront disease suppression.

In ALK-positive NSCLC, disease progression post-recurrence is frequently accompanied by a rapid decline in performance status or severe CNS progression, which heavily restricts subsequent clinical options. Consequently, clinical consensus increasingly emphasizes that delaying initial progression is far more critical than planning subsequent salvage lines of therapy. For this reason, the historical sequential model of utilizing first → second → third-generation agents is increasingly viewed as offering limited overall survival utility.

Because the median PFS achieved with second-line therapies is generally modest (around 6 to 8 months) and disease recurrence severely compromises patient eligibility for subsequent interventions, the broader therapeutic strategy has decisively shifted from 'designing sequential treatment lines' to 'maximizing upfront clinical suppression.' Such changes are the primary background, solidifying Lorviqua's position as the preferred first-line standard of care.

Q. Given these 7-year long-term follow-up results, do you consider that ALK-positive NSCLC can now be classified as a chronic, long-term, manageable condition for certain patients?

The most notable finding of the 7-year follow-up data is the flattening or stabilization of the progression curve following the initial treatment phase. While a certain proportion of patients experience disease progression within the first two years, the progression curve remains remarkably flat thereafter, indicating that the vast majority of remaining patients maintain stable disease control over several years.  

This pattern is fundamentally distinct from conventional chemotherapy models, where disease control steadily deteriorates over time. Instead, it suggests that for a specific subsegment of patients, the disease trajectory can be transformed into a highly stable, long-term clinical state. Therefore, while this does not apply uniformly to all individuals, it is clinically reasonable to approach a subset of patients with the expectation that their condition will be managed as a long-term chronic disease.

Ultimately, the most significant advancement in ALK-positive NSCLC is not merely the extension of survival, but the fundamental alteration of the disease progression pattern in a substantial proportion of patients. This paradigm shift represents the clinical significance of the 7-year CROWN data.