Distinct metastatic spread and progression patterns in patients treated with crizotinib for ROS1- and ALK-rearranged non-small cell lung cancer: a single-center retrospective study

Introduction

Oncogenic rearrangement in C-ros oncogene 1 (ROS1), which is structurally homologous to the tyrosine kinase region of anaplastic lymphoma kinase (ALK), occur in approximately 2% to 3% of NSCLC patients (1,2). Crizotinib, which was first approved for patients with advanced NSCLC with ALK rearrangements, binds with high affinity to ROS1, and potently inhibits ROS1 signaling and cell viability (3-5). In clinical setting, crizotinib produced median PFS duration of 15.8 to 22.8 month in patients with advanced ROS1-positive NSCLC, while the median PFS of 7.7 to 10.9 months in patients with advanced ALK-positive NSCLC, based on the results of several clinical trials (2,6-11). Crizotinib received approval for ROS1-positive NSCLC. Subsequently, entrectinib, a ROS1 tyrosine kinase inhibitor (TKI), was approved for the treatment of ROS1-rearranged NSCLC.

ROS1 rearrangements have been associated with a lower incidence of extrathoracic metastases, including CNS metastases at initial diagnosis and during treatment, compared to ALK rearrangements (12). In contrast, similar frequencies of CNS metastases have been reported in patients with ALK and ROS1 rearrangements (13). ALK rearrangements were associated with pericardial, pleural, and liver metastases compared to EGFR/KRAS/ALK wild-type alterations (14). Additionally, in ALK-positive NSCLC patients, the CNS was the most common metastatic site during crizotinib treatment (15). In ALK-positive NSCLC patients, next-generation ALK inhibitors have been designed to more strongly inhibit the ALK native kinase, be active on crizotinib-induced resistance mutations, and have better blood-brain barrier (BBB) penetration to control or prevent CNS involvement. The second-generation inhibitors, alectinib and brigatinib, have become the standard first-line treatment. In contrast, crizotinib and entrectinib are still the standard of care in ROS1 positive NSCLC patients, but due to the resistance of these TKIs, the development of next-generation ROS1 TKIs is underway.

In this study, to evaluate the distinct clinical features in ROS1- and ALK-positive NSCLC patients, we investigated the baseline metastatic spread, crizotinib efficacy, and progression patterns during crizotinib treatment. This article is presented in accordance with the STROBE reporting checklist (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-23-10/rc).

Methods

Patients

We retrospectively reviewed and included all advanced ROS1- and ALK-positive NSCLC patients who had been treated with crizotinib at the National Cancer Center Hospital from January 2011 to March 2021. There were no exclusion criteria. Data on patient characteristics, metastatic site at the baseline, tumor response to crizotinib, and progression patterns during crizotinib treatment were collected from medical records. ROS1 and ALK rearrangements were identified by fluorescence in situ hybridization, targeted next-generation sequencing, immunohistochemistry, and/or real-time polymerase chain reaction (ROS1 only), as described in previous study (12).

Statistical analysis

PFS was measured as the time from the start of crizotinib treatment to radiographic disease progression (as assessed by the investigator) or death if no disease progression was documented. Patients who survived without documented disease progression were censored at the last follow-up visit. Overall survival (OS) was measured from the initiation of crizotinib treatment to death. Patients with undocumented dates of death were censored from the data of the last visit. Tumor response was assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 (16). The objective response rate (ORR) was defined as the proportion of patients who had a complete response (CR) or partial response (PR). The disease control rate (DCR) was defined as the proportion of patients who achieved CR, PR, or stable disease. Descriptive statistics were used for categorical (frequency and proportion) and continuous variables (median and range). Kaplan-Meier curves and estimates were used to assess the OS, PFS, and cumulative incidence of CNS progression during crizotinib treatment for ROS1- or ALK-positive NSCLC. Differences in OS, PFS, and CNS progression were assessed using log-rank tests. All statistical analyses were conducted using the Statistical Package for Social Sciences (SPSS/Windows, Version 19.0, SPSS Inc., Chicago, USA). All tests were two-tailed, and statistical significance was set at P<0.05. This study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by the Ethics Committee of the National Cancer Center Hospital (No. 2015-355) and individual consent for this retrospective analysis was waived.

Results

Patients characteristics at baseline

We identified 26 ROS1-positive NSCLC and 42 ALK-positive NSCLC patients who had been treated with crizotinib. Patient characteristics are presented in Table 1. The baseline characteristics were similar between both groups. In ROS1-positive NSCLC, crizotinib was administered to 10 patients (38%) as a first-line treatment, 6 patients (23%) as a second-line treatment, and 10 patients (38%) as a third-line or later treatment. In ALK-positive NSCLC, crizotinib was administered to 23 patients (55%) as a first-line treatment, 11 patients (26%) as a second-line treatment, and 8 patients (19%) as a third-line or later treatment (Table 1).

At the baseline, patients with ROS1- and ALK-positive NSCLC had similar intrathoracic metastasis spread (Figure 1A). However, patients with ROS1-positive NSCLC had significantly lower rates of extrathoracic metastases, including CNS metastasis, especially that of extrathoracic lymph node metastases (ROS1, 35%; ALK, 71%; P=0.003; Figure 1B and ROS1, 0%; ALK, 17%; P=0.028; Figure 1C). Regarding CNS metastasis at baseline, three patients with ROS1-positive NSCLC had previously been treated with radiotherapy or surgery, and three patients had untreated brain metastases at the initiation of crizotinib. All of these patients achieved a reduction in brain metastasis with crizotinib. Among patients with ALK-positive NSCLC, 12 had been previously treated for brain metastases before receiving crizotinib, and three had untreated brain metastases at its initiation. The percentage of brain metastases was also lower in ROS1-positive patients, although the difference was not statistically significant (ROS1, 12%; ALK, 29%; P=0.100; Figure 1D).

Figure 1 Frequency of metastatic sites of malignant disease at initial metastatic diagnosis. Frequency of (A) intrathoracic sites, (B) extrathoracic sites including CNS metastases, (C) extrathoracic sites, and (D) brain metastases. ROS1, C-ros oncogene 1; ALK, anaplastic lymphoma kinase; CNS, central nervous system.

Efficacy of crizotinib in ROS1 and ALK-positive NSCLC patients

The ORR and DCR for crizotinib in ROS1-positive patients were 69% and 85%, respectively (Table 2). In ALK-positive patients, the ORR and DCR were 69% and 81%, respectively. There were no significant differences in tumor response and PFS with crizotinib between the two groups (ORR, P=0.987; DCR, P=0.484; median PFS: 10.9 vs. 10.7 months, P=0.232) (Figure 2A). The OS did not significantly differ between ROS1- and ALK-positive NSCLC patients [not reached (95% CI: NR–NR), and 67.7 months (95% CI: 47.6–87.8), respectively (P=0.495)] (Figure 2B).

Figure 2 Kaplan-Meier curves for PFS and OS of patients with ROS1- and ALK-positive NSCLC. (A) PFS with crizotinib treatment (any line of therapy). (B) OS with crizotinib treatment (any line of therapy). PFS, progression-free survival; OS, overall survival; ROS1, C-ros oncogene 1; ALK, anaplastic lymphoma kinase; NSCLC, non-small cell lung cancer.

Progression patterns during crizotinib treatment in ROS1 and ALK-positive NSCLC

Data on progression patterns were available for 16 patients with ROS1-positive and 37 with ALK-positive NSCLC (Figure 3). Progression patterns were similar between the two groups. Brain metastases, including isolated CNS metastasis, were the most common sites of progression in both groups (ROS1, 69%; ALK, 46%; P=0.127). The cumulative incidence of CNS progression in patients with ROS1- and ALK-positive NSCLC during crizotinib treatment is presented in Figure 4. There were no significant differences between the two groups for all patients (P=0.914) or for patients with no CNS metastasis at baseline (P=0.437).

Figure 3 Progression pattern of ROS1- and ALK-positive NSCLC during crizotinib treatment. Frequency of occurrence of (A) intrathoracic and (B) extrathoracic sites, and (C) brain metastases. ROS1, C-ros oncogene 1; ALK, anaplastic lymphoma kinase; CNS, central nervous system; NSCLC, non-small cell lung cancer.

Figure 4 Cumulative incidence of CNS progression (probability) in patients with ROS1- and ALK-positive NSCLC during crizotinib treatment. (A) Cumulative incidence of CNS progression in all patients. (B) Cumulative incidence of CNS progression in patients without brain metastasis at the time of crizotinib initiation. ROS1, C-ros oncogene 1; ALK, anaplastic lymphoma kinase; CNS, central nervous system; NSCLC, non-small cell lung cancer.

Discussion

In this study, we retrospectively evaluated the metastatic spread at baseline and progression patterns during crizotinib treatment in patients with advanced ROS1- and ALK-positive NSCLC. The clinical outcomes of crizotinib were similar in both groups. Additionally, CNS was the most common progression site, and progression patterns during crizotinib treatment in both patient groups were similar.

Two phase II studies evaluating the efficacy of crizotinib in ROS1 fusion-positive NSCLC patients showed that PFS was 15.9 to 22.8 months, while phase III trials revealed that it was 11 months in patients with treatment-naive advanced ALK fusion-positive NSCLC (7,10). Although direct comparison between clinical trials is challenging due to the varying trial designs, the differences in the clinical outcomes with crizotinib treatment between patients with ROS1- and ALK-positive NSCLC could be related to the difference in inhibitory effects of this drug. Indeed, crizotinib had better inhibitory effect on ROS1-dependent cell lines than on ALK-dependent cell lines (1,3). Another reason could be the differences in metastatic spread at baseline. Gainor et al. reported that patients with ROS1-positive disease had significantly lower rates of extrathoracic metastases, including lower rates of brain metastases at the initial metastatic diagnosis, which was consistent with the results of our study (12). Regarding progression patterns during treatment, patients with ROS1-positive NSCLC had a significantly lower cumulative incidence of brain metastases over time. In contrast, Patil et al. reported that there were no statistically significant differences in CNS progression in ROS1- and ALK-positive patients, who were taking crizotinib (13). Our study showed that the progression patterns during crizotinib treatment in ROS1- and ALK-positive NSCLC were similar, and there were no significant differences in the incidence of CNS progression. The difference in the clinical outcomes with crizotinib, including the progression sites, between patients with ROS1- and ALK-positive NSCLC remains controversial.

Crizotinib poorly penetrates the cerebrospinal fluid (CSF) (17). In ALK-positive NSCLC patients, the CNS is the common initial progression site, including isolated progression, and brain metastasis status was significantly associated with both PFS in crizotinib-treated patients and CNS progression. In patients with ROS1-positive NSCLC, it remained unclear how baseline brain metastasis affects the clinical outcomes with crizotinib because two phase II trials evaluating the efficacy of crizotinib treatment in ROS1-positive NSCLC excluded patients with untreated CNS metastases (2,10). The METROS study showed that among six ROS1-positive NSCLC patients with intracranial disease, the intracranial ORR was 33%, and five patients experienced intracranial progression as a pattern of failure (8). In our study, six patients with ROS1-positive NSCLC with brain metastases at baseline, regardless of prior radiotherapy for CNS metastases, and four patients developed CNS progression. Our study showed that the presence of CNS metastasis at baseline in ROS1 fusion-positive NSCLC affected the clinical outcome with crizotinib. Although the biology of brain metastasis is poorly understood, metastases to the CNS, unlike metastases to other distal organ sites, involve the breach of the BBB. BBB effectively prevents the free exchange of substances between the blood and the interstitial fluid of the brain (18-20). The CNS is considered a sanctuary site for metastatic cancer cells because many therapeutic agents cannot cross the BBB. A better understanding of molecular biology of lung cancer metastasis to the brain and efficient drug delivery across the BBB will be essential to find the appropriate treatment strategy for prevention of brain metastasis.

The present study had several limitations. The sample size was small, and the study was conducted in a single institute, which included potential confounders, such as the number of lines of prior treatment and treatment duration. Moreover, although the prognostic impact of distinct fusion genes on clinical outcomes has been reported, details of the fusion types were unavailable (21-23).

Conclusions

We demonstrated that metastatic spread at initial diagnosis differed between patients with ROS1- and ALK-positive NSCLC, but the clinical outcomes with crizotinib treatment and progression patterns, including that of CNS progression, were similar. Continued efforts to develop novel TKIs that can overcome resistance to crizotinib and exhibit better intracranial activity are needed.

Acknowledgments

The authors greatly appreciate the assistance of the staff of the Department of Thoracic Oncology and Division of Molecular Pharmacology of the National Cancer Center Hospital.

Funding: None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-23-10/rc

Data Sharing Statement: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-23-10/dss

Peer Review File: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-23-10/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-23-10/coif). TY reports receiving grants and personal fees from Amgen, AstraZeneca, Ono, Merck Sharp & Dohme, Novartis, Chugai, and Bristol-Myers Squibb; grants from Takeda, Daiichi Sankyo, and AbbVie; and personal fees from Taiho, Eli Lilly, Roche, and ArcherDX outside of the submitted work. KM reports receiving personal fees from Ono Pharmaceutical Co., Ltd., AstraZeneca, Chugai, and Bristol-Myers Squibb, outside of the submitted work. YS reports receiving personal fees from Bristol-Myers Squibb, Chugai, AstraZeneca, and Eli Lilly; grants and personal fees from Ono; and grants from Janssen and Japan Clinical Research Operations K.K. outside of the submitted work. YM reports receiving grants from the National Cancer Center Research and Development Fund, Grant-in-Aid for Scientific Research on Innovative Areas, and Hitachi, Ltd.; grants and personal fees from Olympus; and personal fees from AstraZeneca, Novartis, COOK, AMCO Inc., Thermo Fisher Scientific, Erbe Elektromedizin GmbH, Fujifilm, Chugai, and Eli Lilly outside of the submitted work. Yusuke Okuma reports receiving grants from Roche and AbbVie K.K.; and personal fees from AstraZeneca, Ely Lilly K.K., Bristol-Myers Squibb, Pfizer Taiho Pharma Co. Ltd., AstraZeneca Nippon Boehringer Ingelheim, Chugai Pharma Co. Ltd., Ono Pharma Co. Ltd., and Taiho Pharma Co. Ltd. outside of the submitted work. YG reports receiving grants from AZK, AbbVie, Kyorin, and Preferred Network; grants and personal fees from Pfizer, Eli Lilly, Bristol-Myers Squibb, Ono, Novartis, and Daiichi Sankyo; and personal fees from Chugai, Taiho, Boehringer Ingelheim, Merck Sharp & Dohme, Merck, Thermo Fisher, AstraZeneca, Chugai, Guardant Health Inc., and Illumina outside of the submitted work. HH reports receiving grants and personal fees from Merck Sharp & Dohme, AstraZeneca, Ono, Chugai, Roche, and Novartis; grants from AbbVie, Bristol-Myers Squibb, Merck Biopharma, Daiichi Sankyo, Janssen, and Genomic Health; and personal fees from Eli Lilly and Kyowa-Kirin, outside of the submitted work. NY reports receiving grants from Chugai, Taiho, Eisai, Eli Lilly, Quintiles, Astellas, Bristol-Myers Squibb, Novartis, Daiichi Sankyo, Pfizer, Boehringer Ingelheim, Kyowa-Hakko Kirin, Bayer, Ono Pharmaceutical Co., Ltd., Takeda, Janssen Pharma, Merck Sharp & Dohme, Merck, GlaxoSmithKline, Sumitomo Dainippon, Chiome Bioscience Inc., Otsuka, Carna Biosciences, Genmab, and Shionogi; and personal fees from Ono Pharmaceutical Co., Ltd., Chugai, AstraZeneca, Pfizer, Lilly, Bristol-Myers Squibb, Eisai, Otsuka, Takeda, Boehringer Ingelheim, Cimic, Sysmex, and Eisai, outside of the submitted work. Yuichiro Ohe reports receiving grants, personal fees, and nonfinancial support from AstraZeneca, Chugai, Ono Pharmaceutical Co., Ltd., and Bristol-Myers Squibb; grants and personal fees from Eli Lilly and Pfizer; grants and nonfinancial support from Kyorin; grants from Dainippon-Sumitomo, Taiho, Novartis, Takeda, Kissei, Daiichi Sankyo, Janssen, and LOXO; and personal fees from Boehringer Ingelheim, Bayer, Merck Sharp & Dohme, Taiho, Nippon Kayaku, Kyowa-Hakko Kirin, Celltrion, Amgen, and AnHeeart Therapeutics Inc. outside of the submitted work. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are 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. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by institutional ethics board of National Cancer Center Hospital (No. 2015-355) and individual consent for this retrospective analysis was waived.

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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