Prognostic and Predictive Impact of Creatine Kinase Level in Non-Small Cell Lung Cancer Treated With Tyrosine Kinase Inhibitors

Yu Jiang; Zixuan Su; Yuechun Lin; Yaming Xiong; Caichen Li; Jianfu Li; Runchen Wang; Ran Zhong; Bo Cheng; Jianxing He; Zhanhong Xie; Wenhua Liang


Transl Lung Cancer Res. 2021;10(9):3771-3781. 

In This Article

Abstract and Introduction


Background: The use of tyrosine kinase inhibitors (TKIs) is associated with incident creatine kinase (CK) elevation in the treatment of advanced non-small cell lung cancer (NSCLC) patients. However, whether higher CK levels are associated with better antitumor responses or survival remains to be explored. We intend to investigate the clinical correlation between CK levels and TKI efficacy in advanced NSCLC.

Methods: In this retrospective study, we enrolled 135 patients with stage IV NSCLC receiving TKI-based therapy in our center between June 2012 to July 2020. CK levels were monitored from the initiation of TKI medication and during the administration period. An X-tile analysis provided the optimal cutoff point for higher baseline CK. Patients were identified and grouped according to their baseline CK level and fold changes during TKI therapy. The primary endpoints included progression-free survival (PFS) and overall survival (OS), and the objective response rate (ORR) was calculated as the secondary endpoint.

Results: Among the 135 patients included in our study, those with higher baseline CK levels (≥70 U/L) had favorable PFS (15.2 vs. 8.8 months; P=0.028), while patients with significantly elevated CK (the highest CK value/baseline CK value ≥2 times) appeared to gain better PFS (14.6 vs. 10.0 months; P=0.139). The overall ORR was 67.4%. Patients with higher baseline CK levels had numerically higher ORR (74.6% vs. 60.3%; P=0.076). Similarly, patients with significant CK elevation had a superior 4-month PFS rate (77.6% vs. 59.7%; P=0.029). Results from the subgroup analyses were identical to the overall ones. For patients with higher baseline CK levels, those experiencing significant CK elevation had prolonged PFS (17.2 vs. 14.2 months; P=0.038); a same trend was obtained from the lower baseline CK group (<70 U/L) (9.4 vs. 7.9 months; P=0.038). In multivariable analysis, higher baseline CK level and significant CK elevation remained statistically associated with PFS, with hazard ratios of 0.48 and 0.59, respectively.

Conclusions: Both higher baseline CK levels and significant CK elevation after treatment were correlated with prolonged PFS in NSCLC treated with TKIs, suggesting the potential prognostic and predictive impact of CK level on these patients.


Lung cancer is the second most commonly diagnosed cancer worldwide and the leading cause of global cancer death in 2020. In China, it ranks first in terms of cancer incidence and mortality, and is responsible for over 815,563 new cases and 714,699 deaths, representing approximately one in 5 (17.9%) cancer diagnosed and a quarter of (23.8%) cancer deaths in 2020.[1] Non-small cell lung cancer (NSCLC) accounts for 85% of lung cancer and over 50% of NSCLC patients were diagnosed at an advanced stage.[2]

In the last decade, the discovery of specific oncogenic driver mutations in lung cancer represents valid therapeutic targets and enables individualized targeted treatment that translates into clinically benefit. Specifically, the most common activating mutations in adenocarcinoma include epidermal growth factor receptor (EGFR), which occurs in up to 40% of Asian patients, rearrangements of anaplastic lymphoma kinase (ALK), c-ROS oncogene 1 (ROS-1), and several additional mutations.[3–5] Novel treatment options, such as tyrosine kinase inhibitors (TKIs), have been recommended as first-line therapy for naive and recurrent advanced NSCLC, showing favorable clinical outcomes, enhanced response rate, and greater potency.[6] These include gefitinib, erlotinib, afatinib, and osimertinib for EGFR-mutated NSCLC, alectinib, crizotinib, ceritinib, brigatinib and lorlatinib for ALK-rearranged NSCLC, and crizotinib for ROS-1 mutant NSCLC.[7] TKIs are small molecules that interfere with the kinase activity by competing against ATP binding sites of the catalytic domain in specific oncogenic tyrosine kinases.[8] However, TKIs use in cancer treatment can sometimes result in a certain degree of side effects that affect multiple organs, such as diarrhea, acneiform rash, paronychia, stomatitis, abnormal liver function, and gastrointestinal events.[9–11]

CK elevation is one of the recognized adverse events, which may be attributed to the inhibition of both ABL and AMP-activated protein kinase, occurring in approximately one-third of patients who received TKIs treatment for solid tumors.[12–14] Increasing evidence suggested that serum CK levels may be a potential predictor of development and progression in a variety of cancers, including breast cancer.[15] In addition, CK inactivation has been closely related to the deterioration of oral squamous cell carcinoma (SCC).[16] It is therefore critical that CK levels during TKI therapy be appropriately monitored and managed, as they may provide biochemical indicators of clinical outcome and aid in drug dosage adjustment if necessary. Nonetheless, no clinical studies have been conducted so far to determine whether CK levels are correlated with better clinical outcomes for advanced NSCLC patients treated with TKIs.

In light of those data, we conducted a preliminary analysis in a real-world setting to investigate whether plasma CK levels could be used as independent factors for predicting the prognosis and further identifying the dominant population with the optimal clinical outcome. We present the following article in accordance with the REMARK reporting checklist (available at