Lorlatinib in ALK-positive non-small cell lung cancer: final survival data that reshape the therapeutic landscape

Introduction

The final overall survival (OS) analysis from the pivotal phase II trial of lorlatinib by Ou et al. comes at an opportune time in the management of anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer (NSCLC). After a minimum follow-up of 5 years, this single-arm study reports a remarkable 5-year OS probability of 76% in treatment-naïve ALK-positive patients (EXP1) (1). Even among heavily pretreated cohorts who had failed one or more prior ALK tyrosine kinase inhibitors (TKIs), long-term survival was observed—for example, a 5-year OS of 58% after crizotinib (EXP2-3A) and around 25–27% in those with multiple prior TKIs (EXP4-5 and EXP3B-5) (1). Such outcomes, once unimaginable in metastatic lung cancer, underscore the tremendous progress made with ALK-targeted therapy and set a new benchmark for durability of response. These outcomes by treatment cohort are summarized in Table 1 (1).

Five-year survival in the context of alectinib and brigatinib

The 5-year OS findings with lorlatinib align with the survival improvements achieved by second-generation ALK inhibitors in first-line trials. In the global ALEX trial of alectinib versus crizotinib, the 5-year OS rate was about 62–63% on alectinib (2), with median OS not reached after 4 years of follow-up. Brigatinib showed similar longevity in the ALTA-1L study, with a 4-year OS around 65–66% (3,4). Notably, all these next-generation ALK-TKIs have pushed median OS beyond 5 years, a stark contrast to the crizotinib era. Crizotinib-treated patients had 5-year survival probabilities below 50% in first-line trials (2), largely due to effective post-progression therapies. The fact that lorlatinib’s 5-year OS in a small phase II first-line cohort reached 76%—exceeding historical results with alectinib—is encouraging, though cross-trial comparisons are imperfect. It suggests that maximizing upfront ALK inhibition can translate into prolonged survival, especially when central nervous system (CNS) control is optimized from the start. It is important to note that final OS data from the phase III CROWN trial (lorlatinib vs. crizotinib) are still maturing (5,6). However, at 5 years the progression-free survival (PFS) benefit of lorlatinib is unprecedented: approximately 60% of patients on first-line lorlatinib remain progression-free at 5 years, compared to only ~8% with crizotinib (7). This 5-year PFS of 60% is the highest reported for any ALK inhibitor to date, reflecting lorlatinib’s potent systemic and intracranial activity. Whether this will eventually translate into a significant OS advantage in CROWN is unclear—patients who started on crizotinib often received effective next-line ALK-TKIs, which can diminish OS differences. Nonetheless, the 5-year outcomes firmly establish lorlatinib as a highly efficacious option, prompting debate on its optimal place in therapy. In addition to first-line data, comparison with second-generation TKIs used in the post-crizotinib setting also provides a valuable perspective. In the pooled analysis of two phase II trials, NP28673 and NP28761, alectinib demonstrated a median OS of 26 months and a 5-year OS rate of approximately 24% in crizotinib-pretreated patients (8). Similarly, the ALTA phase II study of brigatinib reported a median OS of 27.6 months in a similar population (9). By contrast, lorlatinib achieved a 5-year OS of 58% in the EXP2-3A cohort of the phase II study (1), which included patients who had progressed on crizotinib. While cross-trial comparisons have limitations, these findings suggest that lorlatinib may offer extended survival even in later-line settings.

First-line vs. sequential use of lorlatinib—sequencing implications

With multiple efficacious ALK-TKIs available, a key question is whether to deploy the most potent drug (lorlatinib) upfront or reserve it for later lines after using second-generation TKIs like alectinib or brigatinib. Proponents of a sequential approach note that advanced ALK-positive NSCLC can be a “forgiving” disease—many patients respond well to initial TKIs and can still derive prolonged benefit from lorlatinib as a salvage therapy (10,11). In this view, the PFS catch-up from sequential therapy might allow comparable total time on treatment while delaying lorlatinib’s unique toxicities. For instance, in the ALEX trial, crossover to alectinib and other TKIs enabled crizotinib-arm patients to achieve long OS despite inferior initial PFS (2). Furthermore, using a less toxic drug first could preserve quality of life early in the disease course. However, emerging real-world evidence argues for front-loading the most effective therapy. An analysis of ALK-TKI sequencing in the United States found that 42% of patients who discontinued first-line alectinib or brigatinib never received any second-line TKI, often due to rapid progression or death (12). Notably, 22% of patients died after first-line discontinuation without receiving second-line therapy (12). As a result, the total time on targeted therapy was limited to roughly 2.5 years in this real-world cohort (12). Additionally, recent real-world studies such as Calles et al. reported a median PFS of only 15.1 months for lorlatinib in ALK-positive patients progressing after a single prior TKI, highlighting the diminished efficacy of lorlatinib in later-line settings (13). These findings underscore that many patients do not get the chance to realize the “sequential” strategy in practice. For such patients, starting on the most potent drug could be life-prolonging. Indeed, the authors of the real-world study conclude that using the TKI with the greatest first-line efficacy upfront is advisable in ALK-positive NSCLC (12). Additionally, sequential ALK-TKI exposure can select for more complex resistance patterns. Laboratory studies have shown that stepwise treatment through first-, second-, and third-generation ALK inhibitors can foster compound ALK mutations that confer high-level resistance to lorlatinib (14-16). In other words, by the time lorlatinib is used after multiple prior TKIs, the cancer may have accumulated multiple on-target mutations (on the same allele) that even lorlatinib cannot overcome. Taking these points together, there is a strong rationale to consider lorlatinib in the first line for appropriate patients, to maximize initial tumor control and possibly avoid the deadliest resistance mechanisms. Ultimately, the sequencing decision should be individualized. Patients with indolent disease or contraindications to lorlatinib might start with a second-generation agent and still do well, whereas those with high-risk disease (e.g., brain metastases or aggressive histology) might benefit from upfront lorlatinib. Ongoing comparisons and longer-term data will further clarify whether an upfront lorlatinib strategy yields superior lifetime outcomes or if sequential therapy can achieve similar OS in a broader population.

Resistance mechanisms and the emerging need beyond ALK

Even with optimized sequencing strategies, resistance to lorlatinib ultimately arises in most patients. In the phase II study, Ou et al. reported that median OS remained unreached in the post-crizotinib cohort (EXP2-3A) but dropped to approximately 20 months in heavily pretreated patients (EXP3B-5) (1), underscoring that tumor progression remains a limiting factor.

A key on-target resistance mechanism to lorlatinib is the development of compound ALK mutations, where two or more kinase domain alterations co-occur on the same allele (14-16). These mutations—such as G1202R in combination with a second-site change—disrupt lorlatinib binding and reduce efficacy. While rare in the crizotinib era, compound mutations have become more frequent with sequential use of second- and third-generation ALK-TKIs, reflecting evolutionary adaptation under stepwise drug pressure (14).

However, in the first-line setting, on-target resistance is less common. Circulating tumor DNA (ctDNA) analysis from the CROWN trial revealed that the majority of patients who progressed on first-line lorlatinib lacked detectable ALK mutations, suggesting ALK-independent (off-target) resistance (6). These may involve bypass signaling [e.g., mesenchymal-epithelial transition (MET) factor, epidermal growth factor receptor (EGFR)], epithelial-mesenchymal transition, or histologic transformation—pathways not addressable by current ALK inhibitors (17-19).

Although several fourth-generation ALK-TKIs (e.g., TPX-0131, NVL-655) are being developed to overcome compound mutations (20,21), their benefit may be limited after first-line lorlatinib failure, where off-target mechanisms predominate. These findings emphasize the importance of routine molecular profiling at progression and the need to explore combination or alternative pathway-directed strategies for post-lorlatinib disease control.

Toxicity profile and management of lorlatinib

A critical aspect of lorlatinib’s use—whether in the first-line or later—is its distinct toxicity profile. As a highly CNS-penetrant TKI, lorlatinib can cause an array of neurologic adverse events (AEs) not typically seen with earlier ALK inhibitors. In the phase II study, virtually all patients experienced some AEs, but most were grade 1–2 (1). The most common treatment-related AEs were hypercholesterolemia (in 84% of patients) and hypertriglyceridemia (68%) (1). Elevations in cholesterol and triglycerides usually occur early and can be substantial, but are manageable with lipid-lowering therapy (statins or fibrates) and dietary modification (22,23). It is recommended to check lipid panels at baseline and periodically during treatment, with prompt initiation of medical therapy for grade 2 or higher hyperlipidemia (24). The other frequent side effects include edema (peripheral edema in ~45% of patients) and weight gain (often >5–10 kg in some patients) (1). Edema is generally mild to moderate, but in some patients—particularly when associated with significant weight gain or functional impairment—it may necessitate dose reduction or temporary interruption (22,23). Supportive measures such as compression stockings and short courses of diuretics are often helpful, but close monitoring is warranted to preserve tolerability. More challenging are lorlatinib’s CNS adverse effects. Approximately 20–25% of patients experience cognitive or mood changes on lorlatinib (1). These can manifest as memory lapses, difficulty with concentration, word-finding trouble, mood swings, irritability, or depression. In most cases, these neuropsychiatric effects are reversible with dose interruption or reduction (1). The phase II trial reported that only 3% of patients required dose reduction specifically for cognitive AEs (1), and serious CNS events were uncommon. Nevertheless, these side effects warrant proactive monitoring. Clinicians often advise patients and families about potential mood or cognitive changes so they can be reported early. If significant CNS symptoms occur, holding lorlatinib for a week or two often leads to improvement; the drug can then be restarted at a lower dose (e.g., 75 mg daily) if needed. In some cases, psychotropic medications (such as selective serotonin reuptake inhibitors for depressive symptoms) or neurocognitive rehabilitation strategies may be employed, though formal guidance is based on limited evidence (23,24). Importantly, no treatment-related deaths occurred in the phase II study (1), and only 5% of patients had to permanently discontinue lorlatinib due to side effects (1). This attests that with careful management—including dose adjustments and supportive care—most patients can continue therapy long-term despite the side effect profile. When considering lorlatinib first-line, the clinician must weigh these chronic toxicities against those of alternatives (alectinib and brigatinib are generally very well tolerated in comparison). Patient preference and comorbidities (e.g., pre-existing hyperlipidemia or psychiatric history) should factor into this decision. In practice, regular follow-up and interdisciplinary care (involving cardiologists for lipid management and neurologists or psychiatrists if needed) can considerably ameliorate the risks (23).

Conclusions

The 5-year survival outcomes from the phase II lorlatinib study represent a landmark in ALK-positive NSCLC. Lorlatinib’s potent intracranial activity and broad-spectrum mutation coverage have extended survival well beyond what was previously achievable (1).

Yet, with its increasing use in the frontline setting, new challenges are emerging. ctDNA analyses suggest that post-lorlatinib progression is often driven by ALK-independent resistance, highlighting the need for rebiopsy, molecular profiling, and novel strategies beyond ALK inhibition.

The future of ALK-targeted therapy lies in anticipating and counteracting resistance through precision sequencing and rational combinations. Lorlatinib has set a new benchmark, and sustaining its success will require continuous innovation at the interface of molecular oncology and clinical care.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the Editorial Office, Translational Lung Cancer Research. The article has undergone external peer review.

Peer Review File: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-466/prf

Funding: None.

Conflicts of Interest: The author has completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-466/coif). Y.K. has received research grant support from the Japan Lung Cancer Society, SGH Foundation, and the Japan Research Foundation for Clinical Pharmacology. These grants were administered through the author’s affiliated institution and are unrelated to the submitted work. The author has no other conflicts of interest to declare.

Ethical Statement: The author is accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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