Abstract
The cyclin-dependent kinase (CDK) 4/6 inhibitors, palbociclib and abemaciclib, have been approved in Japan. However, the selection criteria for these drugs have not been established. Hence, we aimed to identify the risk factors for CDK4/6 inhibitor-induced intolerable adverse events requiring dose reduction or therapy cessation and to establish useful markers for choosing the appropriate CDK4/6 inhibitor, based on the incidence of the intolerable adverse events. This retrospective cohort analysis included patients with advanced breast cancer who received 125 mg/d palbociclib or 300 mg/d abemaciclib. We defined significant adverse events (SAEs) as side effects requiring dose reduction or therapy cessation. Thirty-six percent of the patients who received palbociclib (9/25) and 27.3% of those who received abemaciclib (9/33) experienced SAEs. In palbociclib and abemaciclib groups, baseline white blood cell (WBC) counts and serum albumin (ALB) levels, respectively, were significantly lower in patients who experienced SAEs than in those who did not (palbociclib: p = 0.007; abemaciclib: p = 0.004). According to the receiver operating characteristic curve analysis, the optimal cutoff values for baseline WBC count and ALB level were 5700/µL and 4.0 g/dL, respectively. Among patients with ALB levels >4.0 g/dL, the incidence of abemaciclib-induced SAEs was significantly lower than that of the palbociclib-induced SAEs (1/17 (5.9%) vs. 6/14 (42.9%), odds ratio: 11.0, 95% confidence interval: 1.07–583, p = 0.0281). Thus, a baseline WBC count ≤5700/µL and ALB level ≤4.0 g/dL may be risk factors for palbociclib and abemaciclib-induced SAEs, respectively. Also, high ALB levels can serve as a useful marker for choosing abemaciclib.
INTRODUCTION
Cyclin-dependent kinase (CDK) 4 and CDK6 are downstream enzymes in the estrogen signaling pathway and are involved in the control of cell cycle progression.1) Compared to endocrine therapy alone, endocrine therapy combined with CDK4/6 inhibitors, which interrupt the growth of cancer cells by inhibiting cell cycle progression, improves progression-free survival (PFS) and overall survival in patients with advanced or metastatic breast cancer (MBC).1) Consequently, combinatorial therapy with CDK4/6 inhibitors and endocrine therapy is administered as first-line therapy for patients with estrogen and/or progesterone receptor-positive and human epidermal growth factor receptor 2 (HER2)-negative MBC.1) In Japan, palbociclib and abemaciclib, which are CDK4/6 inhibitors, were approved in December 2017 and November 2018, respectively, and are commonly used.2)
Compared to endocrine monotherapy, endocrine therapy combined with CDK4/6 inhibitors often results in severe adverse effects that lead to the dose reduction or cessation of CDK4/6 inhibitors.2) The toxicity profiles of palbociclib and abemaciclib are different from each other. Neutropenia is a more frequent adverse effect of palbociclib than of abemaciclib2) while diarrhea and liver dysfunction are frequent adverse effects of abemaciclib.3) Palbociclib inhibits CDK6 strongly and more specifically than does abemaciclib. CDK6 is particularly related to the maturation of hematopoietic stem cells in the bone marrow. In contrast, abemaciclib also inhibits CDK9, which is related to intestinal toxicity.2) Diarrhea, liver dysfunction, and febrile neutropenia induced by neutropenia can decrease QOL and increase mortality.3) To prevent severe adverse effects in patients receiving CDK4/6 inhibitors, it is necessary to adjust the drug dose or discontinue the drug while monitoring symptoms and laboratory findings.4)
A head-to-head comparison between palbociclib and abemaciclib has not been reported.3) The National Comprehensive Cancer Network guidelines recommend concomitant use of any CDK4/6 inhibitor as first-line endocrine therapy,5) and currently, the selection of the CDK4/6 inhibitor depends on the judgment of the physician. Although several studies have been conducted to identify predictive biomarkers to facilitate the selection of CDK4/6 inhibitors, such as circulating tumor DNA, none has yet been identified.3) Under these circumstances, it is necessary to identify markers that will allows us to choose the more suitable CDK4/6 inhibitor, thus decreasing unacceptable adverse effects, maintaining patients’ QOL with optimal palliation, and prolonging survival.6,7) Although some studies reported risk factors of adverse effects for each CDK4/6 inhibitor,8,9) whether these risk factors can be used as markers for the selection of appropriate CDK4/6 inhibitors remains to be clarified. The aim of this study was to clarify the risk factors for intolerable adverse effects in patients treated with a combination of a CDK4/6 inhibitor and endocrine therapy and finally identify markers useful for treatment selection, thereby decreasing the frequency of intolerable adverse events and maintaining relative dose intensity.
PATIENTS AND METHODS
Study Design and ParticipantsThis retrospective observational study included patients aged ≥20 years with recurrent or inoperable breast cancer who received palbociclib 125 mg once daily for 21 d during a 28-d cycle, or abemaciclib 150 mg twice daily at Osaka City University Hospital between January 2018 and April 2021. Patients whose blood samples were not available within 30 d preceding the initial administration of palbociclib and abemaciclib, were excluded. This study was approved by the Human Subjects Review Committee of Osaka City University (Approval No. 2021-061).
Significant Adverse EventsSignificant adverse events (SAEs) were defined as side effects that resulted in the dose reduction or cessation of CDK4/6 inhibitors. Cessation due to patients’ wishes because of issues such as psychological or economic problems or side effects apparently not due to the CDK4/6 inhibitor was not considered an SAE. The observation period was defined as 60 d from the initial dose. In cases of dose reduction or cessation due to SAEs, disease progression, or patients’ wishes, observation was censored on the last day of taking CDK4/6 inhibitors.
Data CollectionThe following data were collected from the patients’ medical records: age; sex; body mass index; number of regimens of previous treatment for recurrent or MBC; concomitant endocrine therapeutics; days from the initial dose to the incidence of SAEs; and the most recent laboratory findings, such as WBC and platelet counts, estimated glomerular filtration rate (eGFR), levels of hemoglobin (Hb), aspartate aminotransferase (AST), alanine aminotransferase (ALT), total bilirubin (T-Bil), alkaline phosphatase (ALP), serum albumin (ALB), serum creatinine (Cr), and C-reactive protein.
Statistical AnalysisTo evaluate the association between patient characteristics and SAEs, the Mann–Whitney U test and Fisher’s exact test were used for the analysis of continuous and categorical data, respectively. Receiver operating characteristic (ROC) curve analysis was used to determine the optimal cutoff values if the significant factors were continuous variables. All statistical analyses were performed using EZR version 1.54 (Saitama Medical Center, Jichi Medical University, Saitama, Japan), a graphical user interface for R (The R Foundation for Statistical Computing, Vienna, Austria). p-Values of <0.05 were considered significant.10)
RESULTS
Characteristics of Patients Who Received PalbociclibA CONSORT diagram of the study is shown in Fig. 1. Among the 38 patients who received palbociclib 125 mg/d between January 2018 and April 2021, 13 were excluded from this study owing to a lack of baseline data on at least one of the following factors: WBC and platelet counts; eGFR; and Hb, AST, ALT, T-Bil, ALP, ALB, Cr, and C-reactive protein levels. Accordingly, the palbociclib group included 25 patients. The patients’ baseline characteristics are shown in Table 1. Of these 25 patients, nine (36.0%) experienced SAEs (the SAE group) and 16 (64.0%) did not (the non-SAE group) during the first 60 d of treatment. The main SAE for palbociclib group was neutropenia (n = 9; 100%), and the condition of four patients was complicated by leukopenia (44.4%). The baseline WBC count of the SAE group was significantly lower than that of the non-SAE group (p = 0.007). However, there were no significant differences in other factors. The incidence of SAEs of palbociclib for the interquartile range of the baseline WBC count is shown in Supplementary Table 1. Patients with low baseline WBC counts were more likely to experience SAEs.
Table 1. Baseline Characteristics of the Patients Treated with Palbociclib
| Category | | SAE group (n = 9) | Non-SAE group (n = 16) | p-Value |
|---|
| Female/Male | | 9 / 0 | 16 / 0 | |
| Age (years) | Median [25,75%] | 53 [48, 71] | 57 [53.5, 64.3] | 0.444 |
| BMI | Median [25,75%] | 21.6 [19.2, 24.3] | 21.8 [20.0, 25.0] | 0.610 |
| Number of prior regimens | Median [25,75%] | 1.0 [0.0, 3.0] | 2.0 [1.0, 2.0] | 0.794 |
| Combination therapy | | | | |
| FUL | | 6 | 9 | 1a) |
| FUL + LHRH | | 2 | 3 |
| LET | | 1 | 2 |
| LET + LHRH | | 0 | 1 |
| TAM + LHRH | | 0 | 1 |
| Laboratory data | | | | |
| WBC (/µL) | Median [25,75%] | 4400 [3600, 5200] | 6100 [5400, 7125] | 0.007 |
| Hb (g/dL) | Median [25,75%] | 13.1 [12.2, 13.4] | 13.3 [12.3, 13.9] | 0.444 |
| PLT (*104/µL) | Median [25,75%] | 20.6 [17.1, 22.3] | 25.2 [23.2, 27.2] | 0.084 |
| AST (U/L) | Median [25,75%] | 23.0 [20.0, 23.0] | 23.0 [19.8, 30.5] | 0.932 |
| ALT (U/L) | Median [25,75%] | 14.0 [14.0, 20.0] | 14.5 [12.0, 18.3] | 0.932 |
| T-bil (mg/dL) | Median [25,75%] | 0.60 [0.40, 0.80] | 0.40 [0.38, 0.60] | 0.247 |
| ALP (U/L) (JSCC method) | Median [25,75%] | 204 [183, 238] | 245 [215, 361] | 0.133 |
| ALB (g/dL) | Median [25,75%] | 4.20 [4.00, 4.50] | 4.00 [3.77, 4.23] | 0.201 |
| Cr (mg/dL) | Median [25,75%] | 0.63 [0.56, 0.64] | 0.68 [0.59, 0.69] | 0.281 |
| eGFR (mL/min/1.73 m2) | Median [25,75%] | 79.4 [67.3, 89.0] | 70.2 [64.6, 83.1] | 0.282 |
| CRP (mg/dL) | Median [25,75%] | 0.03 [0.01, 0.40] | 0.08 [0.06, 0.16] | 0.426 |
a) Fisher's exact test. Other: Mann–Whitney U-test. SAE: significant adverse events, BMI: body-mass index, FUL: fulvestrant, LHRH: luteinizing hormone-releasing hormone, LET: letrozol, TAM: tamoxifen, WBC: white blood cell counts, Hb: levels of hemoglobin, PLT: platelet counts, AST: aspartate aminotransferase, ALT: alanine aminotransferase, T-bil: total bilirubin, ALP: alkaline phosphatase, JSCC: Japan Calibration Service System, ALB: serum albumin, Cr: serum creatinine, eGFR: estimated glomerular filtration rate, CRP: C-reactive protein.
ROC curve analysis was performed to determine the optimal cutoff value of baseline WBC count for SAE development, and the identified optimal cutoff value of the above-mentioned factor was 5700/µL (specificity, 62.5%; sensitivity, 100%). The area under the ROC curve (AUC) was 0.830 [95% confidence interval (CI): 0.664–0.995]. The incidence of SAEs was compared between two subgroups obtained by dividing the palbociclib group into two based on this cutoff value: the WBC count ≤5700/µL group (n = 15) and WBC count >5700/µL group (n = 10). The incidence of SAEs of palbociclib in the WBC count ≤5700/µL group was significantly higher than that in the WBC count >5700/µL group [9/15 patients (60.0%) vs. 0/10 patients (0.0%), odds ratio (OR): infinity, 95% CI: 2.13–∞, p = 0.003] (Table 2). The grades of neutropenia within the observation period were compared between the WBC count ≤5700/µL and WBC count >5700/µL groups. The WBC count ≤5700/µL group experienced neutropenia of higher grade than WBC count >5700/µL group (Supplementary Table 2). The grades of leukopenia were not compared because neutropenia could be substituted for leukopenia.
Table 2. The Incidence of SAEs of Palbociclib in the WBC Count ≤5700/µL and WBC Count >5700/µL Groups
| Factor | SAE group (n = 9) | Non-SAE group (n = 16) | OR | 95% CI | p-Value |
|---|
| WBC ≤5700/µL | 9 | 6 | Inf | 2.13-Inf | 0.003 |
| WBC >5700/µL | 0 | 10 |
All: Fisher’s exact test. SAE: significant adverse events, WBC: white blood cell counts, OR: odds ratio, CI: confidence interval, Inf: infinity.
Among the 41 patients who received abemaciclib 300 mg/d between November 2018 and April 2021, eight were excluded from this study owing to baseline data lacking for at least one of the following factors: WBC and platelet counts; eGFR; and Hb, AST, ALT, T-Bil, ALP, ALB, Cr, and C-reactive protein levels. The abemaciclib group included 33 patients (Fig. 1). The patients’ baseline characteristics are shown in Table 3. Of the 33 patients who received abemaciclib, nine (27.3%) experienced SAEs (the SAE group) and 24 (72.7%) did not (the non-SAE group) during the first 60 d of treatment. The main SAEs were ALT elevation (n = 2, 22.2%), fatigue (n = 2, 22.2%), neutropenia (n = 2, 22.2%), anemia (n = 2, 22.2%), and diarrhea (n = 1, 11.1%). In this study, although three abemaciclib-treated patients in the non-SAE group experienced grade 3 diarrhea, they did not need dose reduction or therapy cessation because of an adequate use of antidiarrheal medication. The baseline ALB level in the SAE group was significantly lower than that in the non-SAE group (p = 0.004). However, there were no differences in other factors. The incidence of SAEs of abemaciclib for the interquartile range of the baseline ALB level is shown in Supplementary Table 3. Patients with high baseline ALB levels did not experience SAEs significantly.
Table 3. Baseline Characteristics of the Patients Treated with Abemaciclib
| Category | | SAE group (n = 9) | Non-SAE group (n = 24) | p-Value |
|---|
| Female/Male | | 9 / 0 | 24 / 0 | |
| Age (years) | Median [25,75%] | 71 [67, 74] | 55 [50, 68] | 0.119 |
| BMI | Median [25,75%] | 22.6 [20.3, 24.8] | 22.6 [20.9, 26.2] | 0.983 |
| Number of prior regimens | Median [25,75%] | 0.00 [0.00, 1.00] | 1.00 [0.00, 1.50] | 0.378 |
| Combination therapy | | | | |
| FUL | | 4 | 12 | 0.887a) |
| FUL + LHRH | | 0 | 1 |
| LET | | 5 | 9 |
| LET + LHRH | | 0 | 0 |
| TAM + LHRH | | 0 | 2 |
| Laboratory data | | | | |
| WBC (/µL) | Median [25,75%] | 4800 [3900, 5500] | 5550 [4800, 6075] | 0.188 |
| Hb (g/dL) | Median [25,75%] | 12.4 [10.5, 12.8] | 12.6 [11.7, 13.8] | 0.209 |
| PLT (*104/µL) | Median [25,75%] | 23.9 [19.8, 29.0] | 23.6 [20.5, 30.0] | 0.968 |
| AST (U/L) | Median [25,75%] | 17.0 [15.0, 31.0] | 23.0 [20.8, 25.3] | 0.453 |
| ALT (U/L) | Median [25,75%] | 9.0 [9.0, 26.0] | 17.5 [15.0, 21.8] | 0.145 |
| T-bil (mg/dL) | Median [25,75%] | 0.60 [0.50, 0.60] | 0.50 [0.40, 0.60] | 0.225 |
| ALP (U/L) (JSCC method) | Median [25,75%] | 241 [153, 277] | 272 [171, 332] | 0.342 |
| ALB (g/dL) | Median [25,75%] | 3.90 [3.60, 4.00] | 4.20 [4.00, 4.32] | 0.004 |
| Cr (mg/dL) | Median [25,75%] | 0.68 [0.61, 0.73] | 0.66 [0.57, 0.80] | 0.746 |
| eGFR (mL/min/1.73 m2) | Median [25,75%] | 65.4 [58.8, 79.5] | 67.8 [56.7, 91.6] | 0.599 |
| CRP (mg/dL) | Median [25,75%] | 0.05 [0.04, 0.12] | 0.16 [0.04, 0.39] | 0.407 |
a) Fisher’s exact test. Other: Mann–Whitney U-test. SAE: significant adverse events, BMI: body-mass index, FUL: fulvestrant, LHRH: luteinizing hormone-releasing hormone, LET: letrozol, TAM: tamoxifen, WBC: white blood cell counts, Hb: levels of hemoglobin, PLT: platelet counts, AST: aspartate aminotransferase, ALT: alanine aminotransferase, T-bil: total bilirubin, ALP: alkaline phosphatase, JSCC: Japan Calibration Service System, ALB: serum albumin, Cr: serum creatinine, eGFR: estimated glomerular filtration rate, CRP: C-reactive protein.
The ROC curve analysis revealed the optimal cutoff value for the baseline ALB level predicting SAE development was 4.0 g/dL (AUC: 0.824, specificity: 66.7%, sensitivity: 88.9%, 95% CI: 0.660–0.988). The abemaciclib group was divided into two based on this cutoff value: ALB level ≤4.0 g/dL group (n = 16) and ALB level >4.0 g/dL group (n = 17). The incidence of SAEs of abemaciclib in the ALB >4.0 g/dL group was significantly lower than that in the ALB ≤4.0 g/dL group [1/17 patients (5.9%) vs. 8/16 patients (50.0%) OR: 14.7, 95% CI: 1.54–749, p = 0.007] (Table 4). The grades of ALT elevation, neutropenia, anemia, and diarrhea within the observation period were compared between the ALB level ≤4.0 g/dL and ALB >4.0 g/dL groups, and there were no significant differences between them (Supplementary Table 4). The analysis of the incidence of neutropenia was performed by excluding three patients in the ALB level >4.0 g/dL group whose neutrophil counts were not measured in the observation period. We could not compare the grades of fatigue because many cases of fatigue were not graded.
Table 4. The Incidence of SAEs of Abemaciclib in the ALB Level ≤4.0 g/dL and ALB Level >4.0 g/dL Groups
| Factor | SAE group (n = 9) | Non-SAE group (n = 24) | OR | 95% CI | p-Value |
|---|
| ALB ≤4.0 g/dL | 8 | 8 | 14.7 | 1.54–749 | 0.007 |
| ALB >4.0 g/dL | 1 | 16 |
All: Fisher’s exact test. SAE: significant adverse events, ALB: serum albumin, OR: odds ratio, CI: confidence interval.
We analyzed each of the subgroups to identify the risk factors influencing the incidence of SAEs of palbociclib and abemaciclib. As shown in Fig. 2, in the ALB level >4.0 g/dL group, the incidence of SAEs of abemaciclib was significantly lower than that of the SAEs of palbociclib [1/17 (5.9%) vs. 6/14 (42.9%), OR: 11.0, 95% CI: 1.07–583, p = 0.0281]. In contrast, there were no significant differences in the incidence of SAEs of palbociclib and abemaciclib among the WBC count >5700/µL group [palbociclib: 0/10 (0.00%) vs. abemaciclib: 2/12 (16.7%), OR: 0.00, 95% CI: 0.00–6.35, p = 0.481], WBC count ≤5700/µL group [palbociclib: 9/15 (60.0%) vs. abemaciclib: 7/21 (33.3%), OR: 2.90, 95% CI: 0.626–14.8, p = 0.175], and ALB level ≤4.0 g/dL group [palbociclib: 3/11 (27.3%) vs. abemaciclib: 8/16 (50.0%), OR: 0.389, 95% CI: 0.0481–2.46, p = 0.427].
DISCUSSION
In this study, we investigated the risk factors that can predict the incidence of SAEs of CDK4/6 inhibitors and found that a low WBC count and ALB level are significant factors influencing the incidence of SAEs of palbociclib and abemaciclib, respectively. Additionally, we found that ALB level >4.0 g/dL could be a useful marker for selecting therapy with abemaciclib.
Our study also revealed that the incidence of SAEs was 36.0 and 27.3% in the palbociclib and abemaciclib groups, respectively. Real-world data showed that in palbociclib-treated patients, dose reduction was required in 16.3% of patients and cessation due to adverse events in 3.2% of patients.11) On the other hand, real-world data for abemaciclib showed that the incidence of dose reduction was 6.8% and the rate of cessation due to adverse events was 21.2%.12) Compared to the real-world data, in our study the incidence of SAEs of palbociclib was higher and that of abemaciclib was almost equal. A previous study reported that the trough concentration of palbociclib and incidence of neutropenia were higher in the Asian population than in the non-Asian population.8) Kikuchi et al. reported that 37% of Japanese patients required dose reduction in their case series.13) On the other hand, Toi et al. reported that race was not a significant covariate of pharmacokinetic parameters and concentration of abemaciclib.14) These previous findings are consistent with our results and suggest that the frequent SAEs in the palbociclib group of this study might be attributable to ethnic differences.
Among the palbociclib-treated patients in our study, the incidence of SAEs, all represented by neutropenia, was higher in the WBC count ≤5700/µL group than in the WBC count >5700/µL group. In the PALOMA-3 study, the most common adverse effect of palbociclib was neutropenia followed by leucopenia.15) Because a lower baseline WBC count may be associated with higher incidence of neutropenia and leukopenia, the incidence of the SAEs of palbociclib in the WBC count ≤5700/µL group was higher than that in the WBC count >5700/µL group. In fact, patients in the WBC count ≤5700/µL group experienced higher grade neutropenia. Therefore, it is necessary for palbociclib-treated patients to have more frequent laboratory checks and carefully monitor other possible symptoms.
Meanwhile, although the incidence of each main adverse event assessed as SAE was not significantly different between the ALB level ≤4.0 g/dL and ALB >4.0 g/dL groups, the incidence of abemaciclib-induced SAEs was higher for patients in the ALB level ≤4.0 g/dL group than for those in the ALB level >4.0 g/dL group. According to a phase I clinical trial of abemaciclib, its plasma protein-binding ratio is extremely high (>95%).16) It is well known that an increase in the plasma free concentration of drugs results in increasing efficacy and toxicity.17) Therefore, it is reasonable to suppose that an increase in the plasma free concentration of abemaciclib due to lower ALB levels increases toxicity. In a pharmacokinetics/pharmacodynamics analysis, Tate et al. reported that ALB level affects the exposure and clearance of abemaciclib.16) Interestingly, the analysis also showed that a higher ALB level, in the range of 2.5 to 5.0 g/dL, improved the clearance of abemaciclib. This report supports our results that the cutoff value for the baseline ALB level to select abemaciclib was 4.0 g/dL. The analysis also showed that ALP is a factor influencing the exposure and clearance of abemaciclib.16) It is known that there is a poor correlation between measured values by the Japan Calibration Service System and International Federation of Clinical Chemistry and Laboratory Medicine,18) and therefore our study did not reveal any relationship between ALP and the incidence of abemaciclib SAEs.
In our study, we found that among patients with an ALB level >4.0 g/dL treated with abemaciclib and palbociclib, the incidence of SAEs in the former group of patients was significantly lower than that in the latter group. Because the plasma protein-binding ratio of palbociclib is approximately 85%,19) a lower ALB level should also induce an increase in the plasma free concentration and incidence of SAEs of palbociclib, as well as of abemaciclib. However, this study showed that in the palbociclib-treated patients, patients with an ALB level >4.0 g/dL tended to have a higher incidence of SAEs than did those with an ALB level ≤4.0 g/dL. Sun et al. reported a negative correlation between ALB level and neutrophil count20); consequently, palbociclib-treated patients with a high ALB level were likely to have a lower neutrophil count, leading to myelosuppression and SAEs. Therefore, the incidence of SAEs of palbociclib and abemaciclib might be inversely correlated with ALB levels, and we suggest that ALB level is a predictive factor for selecting abemaciclib depending on patients’ characteristics. Because it is not established that selecting CDK4/6 inhibitors based on ALB levels also decreases the incidence of adverse events except SAEs, careful monitoring of symptoms and management of supportive care are necessary to continue treatment with CDK4/6 inhibitors.
Our study had several limitations. First, because this study was a retrospective single-institution study with a small sample size, the possibility of selection bias could not be excluded, and we could not perform multivariable analysis because of an insufficient number of cases. Second, exclusion of patients whose baseline blood samples were not available within 30 d preceding the initial administration may have led to selection bias. This selection bias might result in the exclusion of characteristic patients, such as those without previous treatment regimens, younger patients, patients with a good performance status, and patients without comorbidities. Third, a previous study reported that a baseline neutrophil count of <3000/µL might be a marker for selecting CDK4/6 inhibitors.13) However, we could not determine which was a better marker, WBC or neutrophil count, because of a lack of neutrophil count. Fourth, the observation period was 60 d. It has been previously reported that neutropenia associated with palbociclib usually occurred within the first 28 d and that associated with abemaciclib within 56 d. The median time to the occurrence of diarrhea due to abemaciclib was 6 d.3) Since most of the adverse effects developed within 60 d, it is a reasonable observation period. However, late adverse events could not be evaluated in this study. Finally, we could not compare the efficacy of palbociclib and abemaciclib because this study involved patients who were concomitantly treated with various endocrine therapies and had various treatment histories.
This study aimed to investigate biomarkers useful for the selection of a particular CDK4/6 inhibitor from the viewpoint of adverse effects; however, previous studies have demonstrated a correlation between efficacy and adverse effects of CDK4/6 inhibitors. Several studies revealed that PFS was maintained irrespective of the dose reduction of palbociclib and abemaciclib,3,21) and the PFS of the patients who experienced grade 3 or 4 neutropenia was longer than that of the patients who experienced neutropenia of grade 1 or 2.8,9) Conversely, another study reported that PFS was longer in patients in whom the palbociclib dose was not reduced.13) Therefore, it is very complicated to select CDK4/6 inhibitors based on only the perspective of reduction of adverse effects because the dose-response relationship is still unknown. Further studies are required to investigate the efficacy and adverse effects of these drugs.
In conclusion, this study clarified that a baseline WBC count ≤5700/µL may be a risk factor for SAEs in patients treated with palbociclib, and baseline ALB level ≤4.0 g/dL may be a risk factor for SAEs in patients treated with abemaciclib. Our findings also suggest that abemaciclib is more tolerable and preferable compared to palbociclib for treating patients with high ALB level.
Acknowledgments
The authors would like to thank all patients who participated in this study and their families as well as the staff of Osaka City University Hospital.
Conflict of Interest
Dr. Takashima reports honoraria from Eisai Co., Ltd., Chugai Pharmaceutical Co., Ltd., Taiho Pharmaceutical Co., Ltd., Pfizer Japan Inc., Daiichi-Sankyo Co., Ltd., and Kyowa Kirin Co., Ltd. All the other authors declare that they have no conflict of interest.
Supplementary Materials
This article contains supplementary materials.
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