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. 2025:43:100905.
doi: 10.1016/j.ctarc.2025.100905. Epub 2025 Mar 22.

Efficacy and safety of lorlatinib in patients with ALK- and ROS1-rearranged metastatic non-small cell lung cancer treated within the compassionate use program in Spain

Antonio Calles  1 , Mirian Alonso  2 , Paloma Martín-Martorell  3 , Ana Gómez  4 , Javier de Castro  5 , Maite Martínez-Aguillo  6 , Anna Estival  7 , Joaquin Mosquera  8 , Natividad Martínez-Banaclocha  9 , Margarita Majem  10 , Roxana Reyes  11 , Eider Azkona  12 , Ana Laura Ortega  13 , Santiago Aguin  14 , Ana Santos  15 , Andrés Aguilar  16 , Marc Cucurull  17 , Ana Blasco  18 , Virginia Calvo  19 , Dolores Isla  20 , Ernest Nadal  21 , Carlos Aguado  22 , Elia Sais  23 , Oscar Juan-Vidal  24 , MPilar Diz-Taín  25 , Álvaro Taus  26 , Noemí Villanueva  27 , Cristina Bayona  28 , Margarita Amenedo  29 , Xabier Mielgo  30 , Esperanza Arriola  31 , Javier Baena  32 ; Spanish Lung Cancer Group
Affiliations
Free article

Efficacy and safety of lorlatinib in patients with ALK- and ROS1-rearranged metastatic non-small cell lung cancer treated within the compassionate use program in Spain

Antonio Calles et al. Cancer Treat Res Commun. 2025.
Free article

Abstract

Background: Lorlatinib, a third-generation tyrosine kinase inhibitor (TKI), targets both ALK and ROS1 rearrangements in non-small cell lung cancer (NSCLC). It is approved for ALK-positive patients after progression on prior TKIs but lacks FDA or EMA approval for ROS1-positive NSCLC. This study evaluates lorlatinib's efficacy and safety in both ALK- and ROS1-positive patients through a compassionate use program in Spain.

Methods: We analyzed ALK-positive patients treated from November 2016 to February 2019 and ROS1-positive patients treated from November 2016 to March 2021. Eligible patients had Stage IV NSCLC with confirmed ALK or ROS1 rearrangements and prior TKI therapy. For ALK-positive patients, at least two prior TKIs were required if crizotinib was used first. For ROS1-positive patients, prior crizotinib was required.

Results: In 61 ALK-positive patients, 59 % had brain metastasis, and 85.2 % received at least two prior ALK TKIs. The overall response rate (ORR) was 32.8 %, with a median progression-free survival (PFS) of 11.2 months. Intracranial ORR was 47.6 %, with higher efficacy in patients with evaluable brain metastasis. In patients with 1, 2, or ≥3 lines of previous TKIs, we observed a median PFS of 15.1, 11.1 and 7.6 months, respectively. Among 42 ROS1-positive patients, 59 % had brain metastasis, and 61.9 % received ≥2 prior therapies. The confirmed ORR was 47.6 %, with 16.7 % complete responses. Median PFS was 10 months. Patients receiving crizotinib alone had a median PFS of 10 months, while those with two prior TKIs had a median PFS of 8.5 months. Intracranial response was 44.4 %, rising to 57.1 % in patients evaluable with brain metastasis. No new safety signals were observed.

Conclusion: Lorlatinib demonstrated consistent efficacy and manageable safety in both ALK- and ROS1-positive NSCLC patients treated under the compassionate use program in Spain. These real-world findings support its use as an effective treatment option in heavily pretreated patients.

Microabstract: We evaluated the efficacy and safety of lorlatinib in ALK- and ROS1-positive NSCLC patients within a compassionate use program in Spain. Among 61 ALK-positive patients, including 59 % with brain metastasis and 85.2 % treated with at least 2 prior ALK TKIs, lorlatinib achieved a confirmed overall response rate (ORR) of 32.8 % and a median progression-free survival (PFS) of 11.2 months. In 42 ROS1-positive patients previously treated with crizotinib, lorlatinib showed an ORR of 47.6 % and a median PFS of 10 months, confirming its clinical activity despite the lack of FDA or EMA approval for this indication.

Keywords: ALK; Anaplastic lymphoma kinase; Brain metastasis; Lorlatinib; Non-small-cell lung cancer; ROS1; Targeted therapy; Tyrosine-kinase inhibitor.

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Conflict of interest statement

Declaration of competing interest AC Consulting fees: AstraZeneca, Boehringer-Ingelheim, Pfizer, Roche/Genentech, Eli Lilly and Company, Novartis, Takeda, Merck Sharp & Dohme, and Bristol Myers Squibb; Research funding: Merck Sharp & Dome. Payment or honoraria: AstraZeneca, Boehringer-Ingelheim, Bayer, Pfizer, Roche, Novartis, Merck Sharp & Dohme, and Bristol Myers Squibb. Support for attending meetings and/or travel:Roche, Boehringer-Ingelheim, Pfizer, Merck Sharp & Dohme, and Bristol Myers Squibb. AG Consulting fees: AstraZeneca, Boehringer-Ingelheim, Pfizer, Roche/Genentech, Eli Lilly and Company, Novartis, Takeda, Merck Sharp & Dohme, and Bristol Myers Squibb. Research funding: Merck Sharp & Dome. Payment or honoraria: AstraZeneca, Boehringer-Ingelheim, Bayer, Pfizer, Roche, Novartis, Merck Sharp & Dohme, and Bristol Myers Squibb. Support for attending meetings and/or travel:Roche, Boehringer-Ingelheim, Pfizer, Merck Sharp & Dohme, and Bristol Myers Squibb. MA Support for attending meetings and/or travel:BMS,MSD,Roche. JC Consulting fees: Astra Zeneca, Bristol Myers Squibb,Hoffmann- La Roche,Merck Sharp and Dohme,Boehringer Ingelheim,Janssen,Lilly,Sanofi,Takeda,Pfizer,Glaxo. Payment or honoraria:Astra Zeneca,Bristol Myers Squibb,Hoffmann- La Roche,Merck Sharp and Dohme,Pfizer,Janssen,Takeda,Sanofi. Support for attending meetings and/or travel: Astra Zaneca,Merck Sharp and Dohme, Hoffmann- La Roche. Advisory Board: Astra Zeneca,Bristol Myers Squibb,Hoffmann- La Roche,Merck Sharp and Dohme,Glaxo,Janssen,Gilead, Sanofi. AA Personal fees: Janssen-Cilag; Takeda Oncology. Support for attending meetings and/or travel: MSD, Janssen-cilag, Roche Farma, BMS AE Payment or honoraria: Pharmamar, GSK, Roche, MSD, AstraZeneca, BMS, Takeda. Support for attending meetings and/or travel: MSD, Pharmamar, Astrazeneca, Boheringer, Takeda. Advisory Board: MSD, Roche, Astrazeneca. SA Consulting fees: Bristol-Myers-Squibb, MERCK, MSD, Grunenthal. Conference payment: Bristol-Myers-Squibb, MERCK. Payment for expert testimony: MERCK. Support for attending meetings and/or travel: MERK, MSD. Advisory Board: MERCK, MSD. AB Consulting fees: Takeda &Sanofi Payment or honoraria: AstraZeneca, Sanofi & Pfizer. Support for attending meetings and/or travel: Takeda, Roche & Janssen. VC Consulting fees: Roche, AstraZeneca, MSD, BMS, Takeda, Sanofi, Amgen. Payment or honoraria: Roche, BMS, MSD, AstraZeneca, Takeda, Pfizer, Janssen. Support for attending meetings and/or travel: AstraZeneca, Roche, MSD, Takeda. EN Grants: Roche, Pfizer, BMS and Merck Serono. Consulting fees: Roche, Bristol Myers Squibb, Merck Sharp Dohme, Merck-Serono, Sanofi, Pfizer, Lilly, Janssen, Amgen, Daiichi-Sankyo, Boehringer-Ingelheim, AstraZeneca, Takeda, Sanofi, Pierre Fabre, Qiagen, and Bayer. Payment or honoraria: Roche, Bristol Myers Squibb, Merck Sharp Dohme, Merck-Serono, Sanofi, Pfizer, Lilly, Janssen, Amgen, Daiichi-Sankyo, Boehringer-Ingelheim, AstraZeneca, Takeda, Sanofi, Pierre Fabre, Qiagen, and Bayer. Support for attending meetings and/or travel: Roche, Takeda, MSD and Pfizer. Advisory Board: Roche, Apollomics and MSD. NV Payment or honoraria: Pfizer & AstraZeneca. CB Payment or honoraria: Sanofi/Regeneron. BMS, AstraZeneca, Pfizer & Roche. Payment for expert testimony: MSD, Roche. Support for attending meetings and/or travel: Roche, MSD, Sanofi/Regeneron, Takeda, Lilly. MA Payment or Honoraria: AZ, Merck, PharmaMar. Support for attending meetings and/or travel: GSK, AZ & MERCK MC Payment or honoraria: Takeda. Support for attending meetings and/or travel: PhamaMar DI Payment or honoraria: Amgen, Janssen, AstraZenecaca, Novartis, BMS, Roche, MSD, Pfizer. Support For Attending Meetings And/Or Travel: AstraZeneca, MSD, Pfizer, Roche, Takeda. Advisory Board: Amgen, AstraZeneca, BMS, Roche, Janssen, Lilly, MSD, Pfizer, Sanofi. CA Payment or honoraria: MSD, Novartis, AstraZeneca, Sanofi, Pfizer. Support for attending meetings and/or travel:Roche, Pierre Fabre, Takeda. Advisory Board: AstraZeneca, BMS, Novartis OJ Consulting fees: Bristol-Myers Squibb, Roche/Genetech, AstraZeneca, Pfizer, Eli Lilly, Takeda, Janssen Payment or honoraria: Boehringer Ingelheim, Bristol-Myers Squibb, Merck Sharp & Dohme, Roche/Genentech, AstraZeneca, Pfizer, Eli Lilly, Takeda, Janssen. Support for attending meetings and/or travel: Takeda, Roche/Genentech, MSD PD Payment or honoraria: BMS, AstraZeneca, Roche, MSD, Takeda, Pfizer, Amgen. Support for attending meetings and/or travel: BMS, Roche, MSD, Takeda. Advisory Board: BMS, AstraZeneca, Boehringer Ingelheim. Other financial or non-financial interests: AstraZeneca, Roche, Mirati, Pfizer. AT Payment or honoraria: Roche, Pfizer, BMS, GSK, AZ, Sanofi. Support for attending meetings and/or travel: GSK XM Payment or honoraria: Novartis, Roche, Pfizer, Astra Zeneca, MSD. Support for attending meetings and/or travel: Roche, Lilly, MSD. Advisory Board: Pfizer, AstraZeneca. Leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid: Grupo Español Transversal de Tumores Huérfanos e Infrecuentes (GETTHI), Grupo Español de Terapias Inmuno-biológicas contra el Cancer (GETICA) EA Payment Honoraria: Bristol-Myers Squib, AstraZeneca, Amgem. Support for attending meetings and/or travel: Bristol-Myers Squibb, Pfizer, Roche The rest of the authors declare no competing interests.

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