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Crizotinib is a first-in-class, orally available anaplastic kinase (ALK) inhibitor that has exhibited impressive clinical activity in ALK-rearranged nonsmall cell lung cancer (NSCLC) in 2 phase 2, single-arm clinical trials. It has also demonstrated significantly improved progression-free survival (PFS) over single-agent chemotherapy as second-line treatment for patients with ALK-rearranged NSCLC in a randomized phase 3 trial. Crizotinib has been approved in many countries for the treatment of ALK-rearranged NSCLC. In addition, as a multitargeted receptor tyrosine kinase (RTK) inhibitor that also can inhibit both the mesenchymal epithelial transition (MET) and ROS1 receptor tyrosine kinases, crizotinib has demonstrated clinical activity in MET-amplified NSCLC and ROS1-rearranged NSCLC.[5, 6] Thus, crizotinib will likely play an expanding role in targeted therapy for NSCLC.
Crizotinib is generally well tolerated, and most of its side effects are in the grade 1 and 2 range. The common side effects reported are transient visual disorders and gastrointestinal upset (nausea, vomiting, diarrhea, or constipation). It has also been reported that there was an average 2.5-beats per minute (bpm) decrease in the heart rate (HR) with every 100-ng/mL increase of serum crizotinib concentration. Indeed, according to the crizotinib package insert, grade 1 and 2 sinus bradycardia (SB) occurred in 5% of patients.
We have observed many patients who had a reduction in their HRs while receiving crizotinib treatment, and a few patients developed asymptomatic SB with an HR <45 bpm. This observation led us to perform a retrospective analysis investigating the frequency, timing, and patient characteristics associated with SB during crizotinib treatment. In addition, we performed an exploratory analysis of a potential correlation between HR changes and response to crizotinib.
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- MATERIALS AND METHODS
- FUNDING SOURCES
The major observation from this single-institution retrospective analysis of HR changes during crizotinib treatment is that HR decrease is a common phenomenon during such treatment. HR decrease has been reported as a pharmacodynamic phenomenon of crizotinib with an average of 2.5 bpm decrease per 100 ng of crizotinib. The average pharmacokinetic level of crizotinib achieved is approximately 280 ng/mL; thus, the average HR decrease should be approximately 8 bpm. We observed that 90% of patients who were receiving crizotinib had a 1-time HR decrease >10 bpm. The average HR decrease for all patients was approximately 26.1 bpm but without any symptoms or ECG changes (such as PR or QTc prolongation). The higher than expected HR decrease observed in this report may reflect individual pharmacokinetic variation or autoinhibition of crizotinib, because crizotinib is a strong cytochrome P450, family 3, subfamily A (CYP3A) inhibitor and also is itself metabolized by CYP3A.
Our exploratory analysis also revealed that patients who experienced SB had a significantly higher response rate and greater cumulative tumor shrinkage during crizotinib therapy, and patients who experience profound SB had the highest response rate and greatest cumulative tumor shrinkage. Patients who experienced profound SB also were on crizotinib treatment the longest. Thus, although this observation raises the possibility of a positive correlation between the magnitude of HR decrease and the extent of clinical benefit from crizotinib, it also may only reflect that the magnitude of HR decrease is a time-dependent or cumulative dose-dependent phenomenon. Nevertheless, it points to the importance for oncologists to try and avoid common medications that can cause HR lowering, such as beta-blockers and calcium channel blockers, during the entire course of crizotinib treatment, because patients can continue to experience HR decrease well into the course of their crizotinib treatment. We want to emphasize that most of our patients were not in permanent SB. Many of these patients alternated between normal sinus rhythm and SB during some of the subsequent clinic visits. Only a few patients were in persistent SB during the majority of clinic visits.
The second observation is that SB from crizotinib is more a reflection of the pretreatment HR rather than a true adverse event per se. We observed that the HR before patients received crizotinib treatment was significantly higher among patients who did not experience SB than among those who experienced SB, whereas there was no statistically significant difference in the average maximum HR decrease between these patient groups. We also observed that older patients and patients with good performance status (conditions that are generally associated with slower HR) were significantly more likely to experience SB while on crizotinib.
Neither CTCAE version 3 nor the newer version 4.0 specifies the HR at which it is considered SB. It is generally defined in cardiology that bradycardia occurs at an HR <60 bpm. However, an oncologist following a patient with ALK-rearranged NSCLC who is deriving clinical benefit from crizotinib and is asymptomatic may not consider an HR ≤59 bpm significant. Because CTCAE grades the severity of SB by the presence or absence of symptoms rather than by the actual lowest recorded HR, we may not appreciate the extent of HR decrease while reading the oncology literature. For example, our 3 previously reported asymptomatic patients who had HRs <45 bpm while on crizotinib all were graded as having grade 1 SB. In the future, we recommend incorporating specific ranges of the HR below 60 bpm in addition to symptoms experienced into the CTCAE grading of SB to allow a better appreciation of the extent of the SB by the oncology community.
It has been demonstrated that crizotinib causes a rapid but reversible drop in testosterone in men, which potentially may result in an HR decrease. Our analysis did not reveal any significant difference in the HR parameters examined and the clinical response to crizotinib between men and women. Thus, decrease in testosterone level is unlikely to be a mechanism that accounts for the HR decrease associated with the receipt of crizotinib. Another potential cause of HR decrease may be hypothyroidism; however, we did not measure thyroid hormone levels in any of our patients, because none of our patients exhibited any signs of hypothyroidism.
The mechanism(s) that allow crizotinib to slow down HR remain unknown. Given our observation that crizotinib lowers the HR without any drop in blood pressure, its effect on the heart is more likely to be chronotropic (which affects the sinoatrial lymph node) or dromotropic (which affects the atrioventricular lymph node) rather than inotropic. Alternatively, the bradycardiac effect of crizotinib may be because of its anti-MET effects, because an analysis of tivantinib, another MET inhibitor, also revealed HR decreases (Lee Rosen, University of California Los Angeles, personal communications).
With all of the limitations of this report, including its retrospective nature, the limited number of patients analyzed, and the recording of the HR at irregularly spaced intervals, depending on scheduled protocol visits, which varied and became less frequent with prolonged crizotinib treatment, it still represents the largest study to date describing HR changes during crizotinib treatment and exploring the potential relation between HR changes and clinical response to crizotinib. Furthermore, the data from this study have undergone extensive queries and quality-control by the clinical trial sponsor (Pfizer Inc., Groton, Conn), because they are part of the data submission to the US Food and Drug Administration in support the orphan drug application and eventual approval of crizotinib in the United States. Our exploratory analysis of a positive correlation of the magnitude of HR decrease with clinical response and tumor shrinkage should be considered only as hypothesis-generating. The PROFILE 1005 study has now enrolled more than 1000 patients with ALK-rearranged NSCLC and may provide a much more robust analysis of the frequency of, timing, patient characteristics associated with, and potential correlation to clinical response with HR changes during crizotinib treatment.