update 15 augustus 2025: 

Uit nieuwe resultaten van de Crown studie blijkt dat een behandeling met lorlatinib een nog langere ziekteprogressievrije overleving en betere ziektecontrole en ook preventie van hersenmetastasen geeft in vergelijking met crizotinib  bij patiënten met niet-kleincellige longkanker (NSCLC) met een ALK = anaplastische lymfoomkinase mutatie. Vooral de ziekteprogressievrije tijd is indrukwekkend beter bij lorlatinib dan bij crizotinib dat ook al een uitstekende resultaten geeft in vergelijking met chemotherapie bv.
 
Het volledige studierapport is nu ook gratis in te zien of te downloaden, zie verderop onderaan dit artikel het abstract enz.

Hier de grafische weergave van de resultaten zoals gepubliceerd juli 2025 (tekst gaat verder onder grafiek):

Graphical abstract undfig1

Resultaten zoals in het abstract weergegeven en vertaalt:

  • Na een mediane follow-up van 62,4 maanden voor lorlatinib en 55,1 maanden voor crizotinib werd de mediane ziekteprogressievrije tijd (PFS) nog niet bereikt (NR, 95%-betrouwbaarheidsinterval : 64,3-NR) versus 9,2 maanden (95%-BI: 7,2-12,7) respectievelijk (gevarenratio = 0,22, 95%-BI: 0,13-0,37);
  • De vijfjaars ziekteprogressievrije tijd (PFS) bedroeg 63% (95%-BI: 49-74) en 7% (95%-BI: 2-17).
  • Het objectieve responspercentage was 81% (95%-BI: 69-90) met lorlatinib en 59% (95%-BI: 46-71) met crizotinib.
  • Bij patiënten met hersenmetastasen bij aanvang was het objectieve responspercentage voor intracraniële progressie 69% (95% BI: 39-91) met lorlatinib en 6% (95% BI: <1-30) met crizotinib.
  • De mediane tijd tot intracraniële progressie was respectievelijk NR (95% BI: NR-NR) en 14,6 maanden (95% BI: 9,2-27,4) (HR = 0,01; 95% BI: <0,01-0,11).
  • De veiligheidsprofielen waren consistent met die van de gehele populatie.

lees verder hieronder:

17 juni 2024: Bron: ASCO 2024, J Clin Oncol 42

Uit de resultaten van de Crown studie blijkt uit de 5-jaars meting dat een behandeling met lorlatinib een nog langere ziekteprogressievrije overleving en betere ziektecontrole en ook preventie van hersenmetastasen geeft in vergelijking met crizotinib  bij patiënten met niet-kleincellige longkanker (NSCLC) met een ALK = anaplastische lymfoomkinase mutatie.

Dat blijkt uit de 5-jaars resultaten van de Crown studie en werden gepresenteerd op ASCO 2024. 

Benjamin Solomon, M.B.B.S., Ph.D., van het Peter MacCallum Cancer Center in Melbourne, Australië, en collega's voerden de fase 3 CROWN-studie uit, waaraan 296 mensen met ALK-positieve niet-kleincellige longkanker (NSCLC) deelnamen die voorheen nog niet eerder waren behandeld.

  • De patiënten werden willekeurig 1:1 toegewezen aan lorlatinib of crizotinib.
  • Ongeveer 25 procent van de deelnemers had hersenuitzaaiingen toen de studie begon. 
  • De onderzoekers ontdekten dat bij een mediane follow-up van 60,2 maanden voor lorlatinib en 55,1 maanden voor crizotinib, de mediane ziekteprogressievrije tijd (PFS) nog niet was bereikt met lorlatinib tegenover 9,1 maanden met crizotinib.
  • De vijfjaars ziekteprogressievrije tijd bedroeg 60 procent met lorlatinib versus 8 procent met crizotinib.
  • De mediane tijd tot intracraniale progressie werd niet bereikt met lorlatinib en bedroeg 16,4 maanden met crizotinib.
  • Bij het analyseren van patiënten met hersenmetastasen bij aanvang vertoonden slechts vier van de 114 patiënten in de lorlatinibgroep hersenprogressie.

Benjamin Solomon tijdens de presentatie: “Deze resultaten van een systemische behandeling, gekoppeld aan bescherming tegen intracraniale progressie en de afwezigheid van nieuwe extra ernstige bijwerkingen, geven aan dat eerstelijns lorlatinib een ongekende verbetering in de resultaten oplevert voor patiënten met gevorderd ALK-positief niet-kleincellige longkanker (NSCLC).
Deze resultaten tonen aan dat lorlatinib de meest effectieve optie is voor nieuw gediagnosticeerde ALK-positieve patiënten met en zonder hersenuitzaaiingen”. 

Het abstract is op ASCO 2024 gepresenteerd:

Lorlatinib vs crizotinib in treatment-naïve patients with advanced ALK+ non-small cell lung cancer: 5-year progression-free survival and safety from the CROWN study.

Authors

person
Benjamin J. Solomon

Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia

Benjamin J. Solomon, Geoffrey Liu, Enriqueta Felip, Tony S. K. Mok, Ross Andrew Soo, Julien Mazieres, Alice Tsang Shaw, Filippo de Marinis, Yasushi Goto, Yi-Long Wu, Dong-Wan Kim, Jean-Francois Martini, Rossella Messina, Jolanda Paolini, Anna Polli, Despina Thomaidou, Francesca Toffalorio, Todd Michael Bauer
Organizations
Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia, Princess Margaret Cancer Centre, Toronto, ON, Canada, Vall d’Hebron University Hospital and Vall d’Hebron Institute of Oncology, Barcelona, Spain, State Key Laboratory of Translational Oncology, Chinese University of Hong Kong, Hong Kong, China, National University Cancer Institute, Singapore, Singapore, Toulouse University Hospital, Toulouse, France, Massachusetts General Hospital Cancer Center, Boston, MA, European Institute of Oncology IRCCS, Milan, Italy, National Cancer Center Hospital, Tokyo, Japan, Guangdong Lung Cancer Institute, Guangdong Provincial People’s Hospital and Guangdong Academy of Medical Sciences, Guangdong, China, Seoul National University College of Medicine and Seoul National University Hospital, Seoul, South Korea, Pfizer Inc., La Jolla, CA, Pfizer, Milan, Italy, Pfizer Inc., Athens, Greece, Tennessee Oncology, Nashville, TN
Abstract Disclosures

Research Funding

Pfizer

Background:
Lorlatinib, a brain-penetrant, 3rd-generation ALK tyrosine kinase inhibitor, demonstrated improved progression-free survival (PFS) and intracranial (IC) activity vs crizotinib in the phase 3 CROWN study in treatment-naïve patients (pts) with advanced ALK+ non-small cell lung cancer (NSCLC). We report long-term efficacy and safety outcomes from the CROWN study after 5 years of follow-up.

Methods:

296 treatment-naïve pts with advanced ALK+ NSCLC were randomized 1:1 to receive lorlatinib 100 mg once daily (n = 149) or crizotinib 250 mg twice daily (n = 147). In this post hoc analysis, we present investigator-assessed efficacy outcomes, safety, and biomarker analyses. Formal statistical testing was not performed.

Results:

As of October 31, 2023, 74 of 149 pts (50%) vs 7 of 142 pts (5%) were still receiving lorlatinib vs crizotinib. With a median duration of follow-up for PFS (95% CI) of 60.2 months (57.4-61.6) in the lorlatinib and 55.1 months (36.8-62.5) in the crizotinib arm, median PFS (95% CI) was not reached (NR; 64.3-NR) with lorlatinib and 9.1 months (7.4-10.9) with crizotinib (HR, 0.19; 95% CI, 0.13-0.27). 5-year PFS (95% CI) was 60% (51-68) with lorlatinib and 8% (3-14) with crizotinib. Median time to IC progression (95% CI) was NR (NR-NR) with lorlatinib and 16.4 months (12.7-21.9) with crizotinib (HR, 0.06; 95% CI, 0.03-0.12).
In pts without baseline brain metastases in the lorlatinib arm, only 4 of 114 developed brain progression, occurring within the first 16 months of treatment. Efficacy outcomes by baseline brain metastases are shown in the Table.

Grade 3/4 adverse events (AEs) occurred in 77% of pts with lorlatinib and in 57% of pts with crizotinib. Treatment-related AEs led to treatment discontinuation in 5% and 6% of pts in the lorlatinib and crizotinib arms, respectively. Safety profile was consistent with that observed in prior analyses.

Emerging new ALK mutations were not detected in circulating tumor DNA collected at the end of lorlatinib treatment (n = 31).

Conclusions:

After 5 years of follow up, the median PFS in the lorlatinib arm has yet to be reached, corresponding to the longest PFS ever reported in advanced NSCLC. Coupled with prolonged IC efficacy and absence of new safety signals, these results indicate an unprecedented improvement in outcomes for pts with advanced ALK+ NSCLC. Clinical trial information: NCT03052608.

With Baseline Brain MetastasesWithout Baseline Brain Metastases
Lorlatinib (n = 35)Crizotinib (n = 38)Lorlatinib (n = 114)Crizotinib (n = 109)
PFS
Median (95% CI), months NR (32.9-NR) 6.0 (3.7-7.6) NR (64.3-NR) 10.8 (9.0-12.8)
HR (95% CI) 0.08 (0.04-0.19) 0.24 (0.16-0.36)
5-year PFS (95% CI), % 53 (35-68) Not estimable 63 (52-71) 10 (5-19)
Time to IC progression
Median (95% CI), months NR (NR-NR) 7.2 (3.7-11.0) NR (NR-NR) 23.9 (16.4-30.8)
HR (95% CI) 0.03 (0.01-0.13) 0.05 (0.02-0.13)
This material on this page is ©2024 American Society of Clinical Oncology, all rights reserved. Licensing available upon request. For more information, please contact licensing@asco.org

After five years of follow-up, lorlatinib efficacy and safety in the Asian subgroup of CROWN continue to be consistent with those in the overall population, with PFS remaining unreached with lorlatinib.

Cover Image - Journal of Thoracic Oncology, Volume 20, Issue 7

Abstract

Introduction

Lorlatinib, a third-generation anaplastic lymphoma kinase inhibitor, reported significantly longer progression-free survival (PFS) than crizotinib in the phase 3 CROWN trial (NCT03052608) in patients with previously untreated advanced anaplastic lymphoma kinase–positive NSCLC. Efficacy was similar in the Asian subgroup. We present an updated subgroup analysis in Asian patients after five years of follow-up.

Methods

Patients were randomly (1:1) assigned to receive lorlatinib 100 mg once daily (n = 59) or crizotinib 250 mg twice daily (n = 61). This post hoc analysis presents updated investigator-assessed efficacy outcomes, safety, and biomarker analyses.

Results

After a median follow-up of 62.4 months for lorlatinib and 55.1 months for crizotinib, median PFS was not reached (NR, 95% confidence interval : 64.3‒NR) and 9.2 months (95% CI: 7.2‒12.7), respectively (hazard ratio = 0.22, 95% CI: 0.13‒0.37); the five-year PFS was 63% (95% CI: 49–74) and 7% (95% CI: 2–17). The objective response rate was 81% (95% CI: 69–90) with lorlatinib and 59% (95% CI: 46‒71) with crizotinib. In patients with baseline brain metastases, the intracranial objective response rate was 69% (95% CI: 39‒91) with lorlatinib and 6% (95% CI: <1‒30) with crizotinib. The median time to intracranial progression was NR (95% CI: NR‒NR) and 14.6 months (95% CI: 9.2‒27.4), respectively (HR = 0.01, 95% CI: <0.01‒0.11). Safety profiles were consistent with the entire population.

Conclusions

After five years of follow-up, lorlatinib efficacy and safety in the Asian subgroup of CROWN continue to be consistent with those in the overall population, with PFS remaining unreached with lorlatinib.

Trial Registration

ClinicalTrials.gov identifier: NCT03052608

CRediT Authorship Contribution Statement

Yi-Long Wu: Data curation, Methodology, Investigation, Formal Analysis, Writing - original draft, Writing - review & editing.
Hye Ryun Kim: Data curation, Investigation, Formal Analysis, Writing - original draft, Writing - review & editing.
Ross A Soo: Data curation, Investigation, Writing - original draft, Writing - review & editing.
Qing Zhou: Data curation, Investigation, Formal Analysis, Writing - original draft, Writing - review & editing.
Hiroaki Akamatsu: Data curation, Investigation, Formal Analysis, Writing - original draft, Writing - review & editing.
Gee-Chen Chang: Data curation, Investigation, Writing - original draft, Writing - review & editing.
Chao-Hua Chiu: Data curation, Investigation, Writing - original draft, Writing - review & editing.
Hidetoshi Hayashi: Data curation, Investigation, Writing - Original Draft, Writing - review & editing.
Sang-We Kim: Data curation, Investigation, Writing - original draft, Writing - review & editing.
Yasushi Goto: Data curation, Methodology, Investigation, Formal Analysis, Writing - original draft, Writing - review & editing.
Terufumi Kato: Data curation, Methodology, Investigation, Formal Analysis, Writing - original draft, Writing - review & editing.
Jianying Zhou: Data curation, Investigation, Writing - original draft, Writing - review & editing.
Victor Ho-Fun Lee: Data curation, Investigation, Writing - original draft, Writing - review & editing.
Makoto Nishio: Data curation, Investigation, Formal Analysis, Writing - original draft, Writing - review & editing.
Baohui Han: Data curation, Investigation, Writing - original draft, Writing - review & editing.
Dong-Wan Kim: Data curation, Investigation, Writing - original draft, Writing - review & editing.
Shun Lu: Data curation, Investigation, Writing - original draft, Writing - review & editing.
Anna Polli: Data curation, Methodology, Investigation, Formal Analysis, Writing - original draft, Writing - review & editing.
Jean-François Martini: Data curation, Methodology, Investigation, Formal Analysis, Writing - original draft, Writing - review & editing.
Francesca Toffalorio: Data curation, Methodology, Investigation, Formal Analysis, Writing - original draft, Writing - review & editing.
Chew Hooi Wong: Formal Analysis, Writing - original draft, Writing - review & editing.
Tony Mok: Data curation, Investigation, Writing - original draft, Writing - review & editing.

Data Availability Statement

On request and subject to review, Pfizer will provide the data that support the findings of this study. Subject to certain criteria, conditions, and exceptions, Pfizer may also provide access to the related individual deidentified participant data. See https://www.pfizer.com/science/clinical-trials/trial-data-and-results for more information.

Declaration of Generative AI and AI-Assisted Technologies in the Writing Process

During the preparation of this work the authors used Pfizer Medical AI Assistant (MAIA) in order to generate the first manuscript draft. After using this tool, the authors reviewed and edited the content as needed and take full responsibility for the content of the publication.

Disclosure

Dr. Wu reports providing advisory services for AstraZeneca, Boehringer Ingelheim, Novartis, and Takeda; receiving personal fees from AstraZeneca, BeiGene, Boehringer Ingelheim, Bristol Myers Squibb, Lilly, MSD, Pfizer, Roche, and Sanofi; and receiving grants from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Hengrui, and Roche, outside the submitted work. Dr. H. R. Kim reports providing advisory services for AstraZeneca and MSD and receiving grants from AstraZeneca, Bristol Myers Squibb, Ono, and Roche, outside the submitted work. Dr. Soo reports consulting for AbbVie, Amgen, AnHeart, AstraZeneca, Bayer, BMS, Boehringer Ingelheim, Daiichi Sankyo, GSK, J INTS BIO, Janssen, Lilly, Merck, Merck Serono, Novartis, Pfizer, Puma, Roche, Sanofi, Taiho, Takeda, Thermo Fisher Scientific, and Yuhan Corporation; receiving honoraria from AbbVie, Amgen, AnHeart, AstraZeneca, Bayer, BMS, Boehringer Ingelheim, Chugai, Daiichi Sankyo, GSK, J INTS BIO, Janssen, Lilly, Merck, Merck Serono, Novartis, Pfizer, Puma, Roche, Sanofi, Taiho, Takeda, Thermo Fisher Scientific, and Yuhan Corporation; and receiving research funding from AstraZeneca, Boehringer Ingelheim, and Pfizer. Dr. Q. Zhou reports receiving honoraria from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Lilly, MSD, Pfizer, Roche, and Hengrui, outside the submitted work. Dr. Akamatsu reports honoraria from Amgen Inc., AstraZeneca K.K., Boehringer Ingelheim Japan, Inc., Bristol Myers Squibb, Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo, Eli Lilly Japan K.K., MSD K.K., Nippon Kayaku Co., Ltd., Novartis Pharma K.K., Ono Pharmaceutical Co., Ltd., Pfizer Inc., Taiho Pharmaceutical Co., Ltd., and Takeda Pharmaceutical Co. Ltd; an advisory role at Amgen Inc., GSK, Janssen Pharmaceutical K.K., and Sandoz; and research funding from Amgen Inc., Chugai Pharmaceutical Co., Ltd., Novartis Pharma K.K., and MSD K.K. Dr. Chiu reports receiving honoraria from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Chugai Pharma, Lilly, MSD, Novartis, Ono Pharmaceutical, Pfizer, Roche, and Takeda and consulting for Lilly, MSD, Novartis, and Roche. Dr. Hayashi has received payment or honoraria from Ono Pharmaceutical, Bristol Myers Squibb, Lilly Japan, Nippon Boehringer Ingelheim, AstraZeneca K.K., Chugai Pharmaceutical, Pfizer Japan, MSD K.K., Novartis, Merck Biopharma, Amgen, Daiichi Sankyo, Takeda Pharmaceutical, 3H Clinical Trial, and Sysmex Corporation; has received research grants from IQVIA Services Japan K.K., Syneos Health Clinical K.K, Nippon Kayaku, MSD K.K., Amgen, Janssen Pharmaceutical K.K., CMIC, Labcorp Development Japan K.K., Kobayashi Pharmaceutical, EP-CRSU, Shionogi & Co., Nippon Boehringer Ingelheim, SRL Medisearch, PRA Health Sciences, Ascent Development Services, Bayer Yakuhin, Astellas Pharma, Bristol Myers Squibb, Eisai, EPS Associates Co Ltd, GSK K.K, Otsuka Pharmaceutical, Pfizer Japan, Pfizer R&D Japan G.K., Taiho Pharmaceutical, Takeda Pharmaceutical, and Chugai Pharmaceutical; and has been part of a patent or has received royalties or licenses from Sysmex. Dr. Goto reports receiving grant support, lecture fees, and advisory board fees from Lilly, Taiho Pharmaceutical, Pfizer, Novartis, MSD, Ono Pharmaceutical, Kyorin Pharmaceutical, and Bristol Myers Squibb; lecture fees and advisory board fees from Chugai Pharmaceutical, Boehringer Ingelheim, and AstraZeneca; grant support and advisory board fees from Guardant Health and Daiichi Sankyo; and advisory board fees from Illumina. Dr. Kato reports providing advisory board services for AbbVie, AstraZeneca, BeiGene, Chugai, Daiichi Sankyo, Janssen, Merck KGaA, MSD, Novartis, and Pfizer; receiving speaker fees from Amgen, AstraZeneca, BeiGene, Boehringer Ingelheim, Bristol Meyers Squibb, Chugai, Daiichi Sankyo, Eli Lilly, GSK, Janssen, Merck KGaA, MSD, Novartis, Ono, Pfizer, Taiho, and Takeda; reports receiving research funding from AbbVie, Amgen, ArriVent, AstraZeneca, Bayer, BeiGene, Blueprint, Boehringer Ingelheim, Bristol Meyers Squibb, Chugai, Daiichi Sankyo, Eli Lilly, Gilead, GSK, Haihe, Janssen, Merck KGaA, MSD, Novartis, Novocure, Pfizer, Regeneron, and Takeda; and has a spouse employed by Eli Lilly. Dr. Lee reports receiving honoraria from Roche, Pfizer, AstraZeneca, Takeda, Novartis, MSD, Lilly, and Amgen and research support grants from AstraZeneca, Pfizer, and Varian Medical Systems. Dr. Nishio reports receiving honoraria from Ono, Chugai, Taiho, Bristol Myers Squibb, Daiichi Sankyo, Lilly, AstraZeneca, MSD, AbbVie, Takeda, Pfizer, Boehringer Ingelheim, Novartis, Nippon Kayaku, Merck, and Janssen. Dr. D-W Kim reports receiving travel support for advisory board meeting attendance from Daiichi Sankyo and Amgen and research funding to the affiliated institution from Alpha Biopharma, Amgen, AstraZeneca/MedImmune, Boehringer Ingelheim, Daiichi Sankyo, Hanmi, Janssen, Pfizer, SK Biopharmaceuticals, Takeda, and Yuhan. Ms. Polli, Dr. Martini, Dr. Toffalorio, and Dr. Wong are employees of Pfizer Inc. and may own stock or stock options in Pfizer. Dr. Mok reports receiving research funding from AstraZeneca, Bristol Myers Squibb, Clovis Oncology, G1 Therapeutics, MSD, Merck Serono, Novartis, Pfizer, Roche, SFJ, Takeda, and Xcovery; receiving speaker fees from ACEA Pharma, Alpha Biopharma Co., Ltd., Amgen, Amoy Diagnostics Co., Ltd., AstraZeneca (before January 2019), Boehringer Ingelheim, Bristol Myers Squibb, Lilly, InMed Medical Communication, MSD, Novartis, Pfizer, prIME Oncology, Roche/Genentech, and Taiho; receiving honoraria from AbbVie, Inc., ACEA Pharma, Alpha Biopharma Co., Ltd., Amgen, Amoy Diagnostics Co., Ltd., AstraZeneca, Bayer, Boehringer Ingelheim, Blueprint Medicines Corporation, Bristol Myers Squibb, Celgene, CStone Pharmaceuticals, Daiichi Sankyo, Lilly, and Fishawack; having shares in Hutchison Chi-Med, and Sanomics Ltd.; and providing advisory board service for AbbVie, Inc., ACEA Pharma, Amgen, AstraZeneca, Bayer, Blueprint Medicine Corporation, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Cirina, CStone Pharmaceuticals, Daiichi Sankyo, Lilly, Fishawack Facilitate, Ltd., G1 Therapeutics, Inc., and GeneDx. The remaining authors declare no conflict of interest.

Acknowledgments

This work was supported by Pfizer Inc. This study was designed by the sponsor (Pfizer), study investigators, and members of the steering committee. Data were collected by investigators and analyzed by the sponsor. The funder of the study contributed to the study design, data collection, data analysis, and data interpretation in collaboration with the authors and provided financial support for editorial and writing assistance. The authors thank the participating patients and their families, including the research nurses, trial coordinators, and operations staff. Editorial and medical writing support was provided by Robyn Roth, PhD, of Nucleus Global and was funded by Pfizer.

Supplementary Data (1)

Supplementary Material

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Brigatinib versus crizotinib in ALK inhibitor-naive advanced ALK-positive NSCLC: final results of phase 3 ALTA-1L trial
J Thorac Oncol. 2021; 16:2091-2108

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Tyrosine Kinase Remmers (TKR) >> Afatinib, een Tyrosine kinase >> Alectinib geeft uitstekende >> Amivantamab + lazertinib samen >> Crizotinib is superieur aan >> Ensartinib geeft nog betere >> Lorlatinib geeft veel langere >> Osimertinib aanvullend op >> Poziotinib geeft complete >> Sotorasib verbetert ziekteprogressievrije >>