Long-term efficacy and improved overall survival of lorlatinib in anaplastic lymphoma kinase-rearranged lung cancer: is cure a dream or a reality?
Editorial Commentary

Long-term efficacy and improved overall survival of lorlatinib in anaplastic lymphoma kinase-rearranged lung cancer: is cure a dream or a reality?

Yoshitsugu Horio1,2 ORCID logo, Hiroaki Kuroda3, Eiichi Sasaki4, Katsuhiro Masago4

1Department of Outpatient Services, Aichi Cancer Center Hospital, Nagoya, Japan; 2Department of Thoracic Oncology, Aichi Cancer Center Hospital, Nagoya, Japan; 3Department of Thoracic Surgery, Teikyo University Hospital, Mizonokuchi, Kanagawa-prefecture, Japan; 4Department of Pathology and Molecular Diagnostics, Aichi Cancer Center Hospital, Nagoya, Japan

Correspondence to: Yoshitsugu Horio, MD, PhD. Department of Outpatient Services, Aichi Cancer Center Hospital, Nagoya, Japan; Department of Thoracic Oncology, Aichi Cancer Center Hospital, 1-1 Kanokoden, Chikusa-ku, 464-8681 Nagoya, Japan. Email: yhorio@aichi-cc.jp.

Comment on: Ou SI, Solomon BJ, Besse B, et al. Final Overall Survival and Long-Term Safety of Lorlatinib in Patients With ALK-Positive NSCLC From the Pivotal Phase 2 Study: A Brief Report. J Thorac Oncol 2025;20:513-20.

Keywords: Non-small cell lung cancer (NSCLC); anaplastic lymphoma kinase-rearrangement (ALK-rearrangement); tyrosine kinase inhibitor (TKI); lorlatinib

Submitted Apr 14, 2025. Accepted for publication Jun 23, 2025. Published online Jun 26, 2025.

doi: 10.21037/tlcr-2025-694

With advances in genome analysis, many driver gene mutations have been identified in non-small cell lung cancer (NSCLC), including mutations in EGFR, KRAS, BRAF, HER2, and MET, as well as rearrangements in ALK, ROS1, RET, NTRK, and NRG1 genes. Targeted therapies against these alterations have significantly improved outcomes in metastatic NSCLC. The EML4-ALK fusion, discovered in 2007, is found in 3–7% of NSCLC (1). Crizotinib, originally developed as a MET inhibitor, was the first anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI) and demonstrated clinical benefit; however, resistance limited its durability (1-4). This led to second-generation ALK TKIs (alectinib, ceritinib, brigatinib, ensartinib), and third-generation lorlatinib (1,5). Envonalkib and iruplinalkib, approved in China, also show multikinase inhibition with ALK inhibitory activity. While second-generation ALK TKIs target specific mutations, lorlatinib is effective against all known single ALK resistance mutations, including G1202R (against which brigatinib also retains activity). However, lorlatinib is ineffective against compound mutations (2) or novel on-target or off-target resistance mechanisms that may emerge. Despite high response rates, ALK TKIs differ in potency, resistance profiles, kinase selectivity, and central nervous system (CNS) penetration (2,3,5).

Recently, long-term overall survival (OS) data from the phase II trial of lorlatinib were reported (4). This trial primarily enrolled ALK-positive NSCLC patients treated with lorlatinib 100 mg once daily, grouped into five expansion cohorts (EXPs) based on prior treatment history: treatment-naïve (n=30; EXP1), post-crizotinib (n=27; EXP2), crizotinib plus chemotherapy (n=32; EXP3A), one second-generation ALK TKI ± chemotherapy (n=28; EXP3B), two ALK TKIs ± chemotherapy (n=65; EXP4), and three ALK TKIs ± chemotherapy (n=46; EXP5). The primary endpoint was objective response rate (ORR); secondary endpoints included OS and safety. Notably, the 5-year OS rate in the treatment-naïve cohort was 76%. Additionally, in the phase III CROWN trial, lorlatinib achieved a 5-year progression-free survival (PFS) rate of 60%, compared to 8% with crizotinib (6). The primary endpoint in the CROWN trial was PFS, with ORR and intracranial ORR (IC-ORR) as secondary endpoints. Clinical efficacy data of these phase II and III trials, along with results from seven other phase III trials, are summarized in Table 1 (4,6-17).

Table 1

ALK TKIs for advanced NSCLC patients in pivotal clinical trials

Characteristics Lorlatinib Lorlatinib Alectinib Brigatinib Ceritinib Ensartinib Iruplinalkib Envonalkib Crizotinib
Trial Phase 2 study EXP1 CROWN ALEX ALTA-1 ASCEND-4 eXalt3 INSPIRE Phase 3 study PROFILE-1014
Comparator None Crizotinib Crizotinib Crizotinib Platinum + pemetrexed Crizotinib Crizotinib Crizotinib Platinum + pemetrexed
ORR (%) 90 76 82.9 74 72.5 75 93 81.68 74
Median PFS (months) 17.7 NR 34.8 24 16.6 Not reported 36.8 24.87 10.9
Landmark PFS (%) Not reported 70 (2-year) 56.6 (2-year) 48 (2-year) Not reported 54.2 (2-year) 60.9 (2-year) Not reported Not reported
65 (3-year) 46.4 (3-year) 43 (3-year)
63 (4-year) 43.7 (4-year) 36 (4-year)
60 (5-year)
HR for PFS versus crizotinib (95% CI) Not applicable 0.19
(0.13–0.27)		 0.43
(0.32–0.58)		 0.48
(0.35–0.66)		 Not applicable 0.45
(0.3–0.66)		 0.292
(0.199–0.43)		 0.47
(0.34–0.64)		 Not applicable
Median OS (months) NR NR NR NR Not reported NR Not reported Not reported NR
Landmark OS (%) Not reported 72.5 (2-year) 76 (2-year) 70.6 (2-year) 78 (2-year) 85.6 (2-year) 78.4 (2-year)
76 (5-year) 62.5 (5-year) 66 (4-year) 56.6 (4-year)
HR for OS versus crizotinib (95% CI) Not applicable 0.72
(0.41–1.25)		 0.67
(0.46–0.98)		 0.81
(0.53–1.22)		 Not applicable 0.91
(0.54–1.54)		 0.95
(0.53–1.69)		 Not reported Not applicable
IC-ORR for measurable metastasis (%) 66.7 82 81 78 72.7 Not reported 90.9 78.95 Not reported
HR for intracranial progression versus crizotinib (95% CI) Not applicable 0.06
(0.03–0.12)		 Baseline CNS (+) 0.18 (0.09–0.36) 0.44
(0.3–0.65)		 Not applicable Not reported 0.39
(0.18–0.81)		 Not reported Not applicable
Baseline CNS (−) 0.14 (0.06–0.33)

ALK, anaplastic lymphoma kinase; CI, confidence interval; CNS, central nervous system; EXP1, expansion cohort 1; HR, hazard ratio; IC-ORR, intracranial ORR; NSCLC, non-small-cell lung cancer; NR, not reached; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; TKI, tyrosine kinase inhibitor.

Although direct comparisons across clinical trials must be made with caution, the 5-year OS of 76% in treatment-naïve patients from the phase II lorlatinib trial is notable, particularly compared to the 5-year OS of 62.5% in the ALEX trial and the 4-year OS of 66% in the ALTA-1 trial (3,9,11). Detailed OS data from the CROWN trial remains pending until the second interim analysis. Moreover, the 5-year PFS of 60% in the CROWN trial is impressive (7), especially in comparison to 4-year PFS rates of 43.7% and 36% in the ALEX and ALTA-1 trials, respectively (9,11). Long-term landmark PFS data are not available for other ALK TKIs. Among patients with measurable brain metastasis, the IC-ORR of lorlatinib was 82% versus 23% for crizotinib in the CROWN trial (Table 1) (6). IC-ORRs for alectinib, brigatinib, ceritinib, iruplinalkib, and envonalkib were 81%, 78%, 72.7%, 90.9%, and 78.95%, respectively (8,11,12,14,16). Although most ALK TKIs (except crizotinib) show high IC-ORRs (4,6,8,11-14,16), the hazard ratio of 0.06 for intracranial progression with lorlatinib versus crizotinib in the CROWN trial is particularly striking (Table 1). These findings suggest that first-line lorlatinib offers superior control of brain metastases and long-term survival benefits—albeit with challenging adverse events, including neurocognitive dysfunction, hyperlipidemia, hypertension, and weight gain. Indeed, prior to the publication of the CROWN trial, alectinib—valued for its efficacy and favorable safety profile—was commonly used first-line in Japan, with sequential ALK TKI strategies preferred.

Lorlatinib was designed to overcome the ALK on-target mutation, G1202R, and was formulated to evade P-glycoprotein-mediated efflux (1,18). Its enhanced blood-brain barrier penetration is attributed to suppression of secreted phosphoprotein 1 (SPP1) and inhibition of vascular endothelial growth factor (VEGF), transforming growth factor-beta (TGF-beta), and claudin, thereby reducing the number of tight junctions between blood-brain barrier cells and increasing CNS drug concentrations (18). In advanced solid tumors, targeted therapies often induce incomplete tumor responses, allowing drug-tolerant persister (DTP) cells to evolve into drug-resistant (DR) cells (19). The extended PFS and OS observed with lorlatinib may reflect reduced emergence of DTP or DR cells. However, elucidating ALK TKI resistance mechanisms remains challenging due to the low detection rate of circulating tumor deoxyribonucleic acid (ctDNA) and the difficulty of rebiopsy (20). Nonetheless, comprehensive molecular characterization via tissue and/or liquid biopsy is crucial for optimizing treatment sequences and maximizing combined PFS1 and PFS2 after progression on first-line therapy. Resistance mechanisms include both on-target and off-target pathways. Off-target resistance arises through bypass pathway activation, histologic transformation, drug efflux, and so on (1,18). These resistance mechanisms vary across ALK TKI generations, with lorlatinib showing lower on-target mutation rates (25–30%) compared to earlier generation TKIs (1). The incidence of compound ALK mutations rises from 23% in alectinib progressors (regardless of prior ALK TKIs) to 48% in patients treated with sequential second-generation TKIs followed by lorlatinib (21). Most lorlatinib-associated on-target compound mutations are often refractory to currently available ALK TKIs. To address this, the phase I/II ALKOVE-1 trial of NVL-655, a fourth-generation ALK TKI with high selectivity, broad activity against ALK G1202R single and compound mutations and strong CNS penetration, has recently demonstrated clinical activity in heavily pretreated patients with ALK-positive NSCLC (2). Additionally, proteolysis-targeting chimeras (PROTACs) targeting ALK mutations represent a promising strategy (1,18).

Regarding off-target resistance, MET amplification is observed in 22% of lorlatinib-resistant cases (1,18). MET or MEK inhibitors in combination with ALK TKIs are under investigation. Other emerging strategies include antibody-drug conjugates (ADCs) targeting trophoblast cell-surface antigen (Trop2), which is expressed in over 60% of adenocarcinomas and around 75% of squamous cell carcinomas and shows promise in ALK-positive NSCLC (18). While immune checkpoint inhibitor (ICI) monotherapy has limited efficacy, a novel immune-based approach involving the use of ALK as a vaccine target is being explored (1,18). However, the heterogeneity of resistance—often involving concurrent on-target and off-target mechanisms across metastatic sites—complicates management. In such cases, local consolidative therapies, such as surgical resection, stereotactic radiation therapy (SRT), radiofrequency ablation (RFA), and cryotherapy, may be effective in controlling oligo-progressive or oligo-residual disease (18). In selected cases, these approaches may even enable treatment-free remission (TFR) or even cure (22).

Several critical clinical questions remain. First, TP53 mutations, found in around 40% of advanced ALK-positive NSCLC, are associated with significantly shorter median PFS when treated with alectinib, brigatinib, or lorlatinib (3). Similarly, the EML4-ALK variant 3 (3a/3b) is a poor prognostic factor (3). Thus, lorlatinib may be suboptimal as first-line therapy in these subgroups. Should we conduct head-to-head trials comparing lorlatinib with fourth-generation TKIs such as NVL-655? Should lorlatinib be combined with chemotherapy, ADC, or immunotherapy to improve OS? Should we await results from second-line trials of fourth-generation ALK TKIs or subgroup analyses in first-line settings? Second, what mechanisms underlie intrinsic resistance—apart from TP53 mutation or EML4-ALK variant 3—in 10–30% of patients who progress within 3–4 months of initiating ALK TKIs (6). Third, could patients with long-term, prolonged PFS and positron emission tomography (PET)-negative disease achieve TFR or even cure after ALK TKI discontinuation, similar to selected chronic myeloid leukemia (CML) patients treated with TKIs? In ALK-positive resectable stage IIB–IIIB NSCLC treated with 6–32 weeks of neoadjuvant alectinib, 7 of 12 patients were reported to achieve pathologic complete response (pCR) (23). In locally-advanced/metastatic NSCLC treated with 6–70 weeks of alectinib, 5 and 9 of 10 patients achieved pCR and major pathologic response (MPR), respectively, with one out of two metastatic patients showing N2M1 to N0M0 conversion (24). In contrast, the phase III Neo-ADAURA trial (stage II–IIIB EGFR-mutated NSCLC) with three cycles of preoperative osimertinib ± chemotherapy reported pCR rates of only 4% (combination group) and 9% (monotherapy group) (25). These results suggest that alectinib may produce higher pCR rates than osimertinib for resectable NSCLC. Alectinib is now being evaluated in perioperative phase II trials (ALNEO, NAUTIKA1), which may redefine treatment for ALK-positive resectable NSCLC (23). Targeted therapies often fail to eliminate all tumor cells, allowing DTP cells to evolve into DR cells (19). Tumor microenvironments in the lung, liver, and brain may also support these cells. Among advanced ALK-positive NSCLC patients with more than 5-year PFS, 5–30% were treated with crizotinib or second-generation TKIs, and about 60% with lorlatinib (7,9), PET-negative patients might be potential candidates for TFR or cure. Should surgical resection of the primary lung tumor be considered in such patients to eliminate DTP and/or DR cells in lung microenvironments supporting tumor cell survival? Finally, with lorlatinib extending median PFS beyond 5 years in advanced ALK-positive NSCLC, strategies such as perioperative ALK TKI use for resectable disease or integration into multimodal therapy for locally advanced disease warrant serious consideration.

Basic, translational and clinical research is actively exploring novel agents and combinations targeting EML4-ALK and resistance pathways, with the ultimate goal of achieving a cure. While lorlatinib has significantly improved outcomes in advanced ALK-positive NSCLC, achieving a cure will likely require creative and strategic integration of multimodal therapies.

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-2025-694/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-694/coif). The authors have no conflicts of interest to declare.

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References

  1. Voena C, Ambrogio C, Iannelli F, et al. ALK in cancer: from function to therapeutic targeting. Nat Rev Cancer 2025;25:359-78. [Crossref] [PubMed]
  2. Lin JJ, Horan JC, Tangpeerachaikul A, et al. NVL-655 Is a Selective and Brain-Penetrant Inhibitor of Diverse ALK-Mutant Oncoproteins, Including Lorlatinib-Resistant Compound Mutations. Cancer Discov 2024;14:2367-86. [Crossref] [PubMed]
  3. Lee ATM, Ou SI. Overcoming Central β-Sheet #6 (Cβ6) ALK Mutation (L1256F), TP53 Mutations and Short Forms of EML4-ALK v3/b and v5a/b Splice Variants are the Unmet Need That a Re-Imagined 5th-Generation (5G) ALK TKI Must Deliver. Lung Cancer (Auckl) 2024;15:19-27.
  4. Ou SI, Solomon BJ, Besse B, et al. Final Overall Survival and Long-Term Safety of Lorlatinib in Patients With ALK-Positive NSCLC From the Pivotal Phase 2 Study: A Brief Report. J Thorac Oncol 2025;20:513-20. [Crossref] [PubMed]
  5. Ou SI, Lee ATM, Nagasaka M. From preclinical efficacy to 2022 (36.7 months median follow -up) updated CROWN trial, lorlatinib is the preferred 1st-line treatment of advanced ALK+ NSCLC. Crit Rev Oncol Hematol 2023;187:104019. [Crossref] [PubMed]
  6. 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;383:2018-29. [Crossref] [PubMed]
  7. 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;42:3400-9. [Crossref] [PubMed]
  8. 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;377:829-38. [Crossref] [PubMed]
  9. Mok T, Camidge DR, Gadgeel SM, et al. Updated overall survival and final progression-free survival data for patients with treatment-naive advanced ALK-positive non-small-cell lung cancer in the ALEX study. Ann Oncol 2020;31:1056-64. [Crossref] [PubMed]
  10. Camidge DR, Kim HR, Ahn MJ, et al. Brigatinib versus Crizotinib in ALK-Positive Non-Small-Cell Lung Cancer. N Engl J Med 2018;379:2027-39. [Crossref] [PubMed]
  11. Camidge DR, Kim HR, Ahn MJ, et al. Brigatinib Versus Crizotinib in ALK Inhibitor-Naive Advanced ALK-Positive NSCLC: Final Results of Phase 3 ALTA-1L Trial. J Thorac Oncol 2021;16:2091-108. [Crossref] [PubMed]
  12. Soria JC, Tan DSW, Chiari R, et al. First-line ceritinib versus platinum-based chemotherapy in advanced ALK-rearranged non-small-cell lung cancer (ASCEND-4): a randomised, open-label, phase 3 study. Lancet 2017;389:917-29. [Crossref] [PubMed]
  13. Horn L, Wang Z, Wu G, et al. Ensartinib vs Crizotinib for Patients With Anaplastic Lymphoma Kinase-Positive Non-Small Cell Lung Cancer: A Randomized Clinical Trial. JAMA Oncol 2021;7:1617-25. [Crossref] [PubMed]
  14. Shi Y, Chen J, Yang R, et al. Iruplinalkib (WX-0593) Versus Crizotinib in ALK TKI-Naive Locally Advanced or Metastatic ALK-Positive NSCLC: Interim Analysis of a Randomized, Open-Label, Phase 3 Study (INSPIRE). J Thorac Oncol 2024;19:912-27. [Crossref] [PubMed]
  15. Shi YK, Chen J, Yang R, et al. 1278P Update of the INSPIRE study: Iruplinalkib versus crizotinib in ALK TKI-naïve locally advanced or metastatic ALK+ non-small cell lung cancer (NSCLC). Ann Oncol 2024;35:S815. [Crossref] [PubMed]
  16. Yang Y, Min J, Yang N, et al. Envonalkib versus crizotinib for treatment-naive ALK-positive non-small cell lung cancer: a randomized, multicenter, open-label, phase III trial. Signal Transduct Target Ther 2023;8:301. [Crossref] [PubMed]
  17. Solomon BJ, Mok T, Kim DW, et al. First-line crizotinib versus chemotherapy in ALK-positive lung cancer. N Engl J Med 2014;371:2167-77. [Crossref] [PubMed]
  18. Poei D, Ali S, Ye S, et al. ALK inhibitors in cancer: mechanisms of resistance and therapeutic management strategies. Cancer Drug Resist 2024;7:20. [Crossref] [PubMed]
  19. He J, Qiu Z, Fan J, et al. Drug tolerant persister cell plasticity in cancer: A revolutionary strategy for more effective anticancer therapies. Signal Transduct Target Ther 2024;9:209. [Crossref] [PubMed]
  20. Aredo JV, Jamali A, Zhu J, et al. Liquid Biopsy Approaches for Cancer Characterization, Residual Disease Detection, and Therapy Monitoring. Am Soc Clin Oncol Educ Book 2025;45:e481114. [Crossref] [PubMed]
  21. Ou SI, Nagasaka M, Brazel D, et al. Will the clinical development of 4th-generation "double mutant active" ALK TKIs (TPX-0131 and NVL-655) change the future treatment paradigm of ALK+ NSCLC? Transl Oncol 2021;14:101191. [Crossref] [PubMed]
  22. Horio Y, Mizuno T, Sakao Y, et al. Successful salvage surgery following multimodal therapy in a patient who harboured ALK-rearranged advanced lung adenocarcinoma with multiple organ metastases. Respirol Case Rep 2019;7:e00451. [Crossref] [PubMed]
  23. Cortinovis DL, Leonetti A, Morabito A, et al. Alectinib in Early-Stage Anaplastic Lymphoma Kinase-Positive Non-Small Cell Lung Cancer: Current Evidence and Future Challenges. Cancers (Basel) 2024;16:2610. [Crossref] [PubMed]
  24. Lococo F, Cancellieri A, Chiappetta M, et al. Salvage Surgery After First-Line Alectinib for Locally-Advanced/Metastatic ALK-Rearranged NSCLC: Pathological Response and Perioperative Results. Clin Lung Cancer 2023;24:467-73. [Crossref] [PubMed]
  25. He J, Tsuboi M, Weder W, et al. Neoadjuvant Osimertinib for Resectable EGFR-Mutated Non-Small Cell Lung Cancer. J Clin Oncol 2025; Epub ahead of print. [Crossref]
Cite this article as: Horio Y, Kuroda H, Sasaki E, Masago K. Long-term efficacy and improved overall survival of lorlatinib in anaplastic lymphoma kinase-rearranged lung cancer: is cure a dream or a reality? Transl Lung Cancer Res 2025;14(6):2353-2358. doi: 10.21037/tlcr-2025-694

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