The impact of ethnicity on efficacy and toxicity of cyclin D kinase 4/6 inhibitors in advanced breast cancer: a meta-analysis
Abstract
Purpose Adding cyclin-dependent kinase (CDK) 4/6 inhibitor to endocrine therapy improves progression-free survival (PFS) in advanced breast cancer but the impact of ethnicity on efficacy and toxicity is unclear. We aimed to estimate the relative treatment efficacy and toxicity of endocrine therapy with and without CDK4/6 inhibitors, and compare between Asian/non-Asian subgroups.Method This meta-analysis included published first-line randomized trials comparing CDK4/6 inhibitor-endocrine therapy versus endocrine monotherapy. Hazard ratios (HR) and 95% confidence intervals (CI) for the overall population and Asian/ non-Asian subgroups were extracted. The inverse-variance-weighted method was used to pool treatment estimates of PFS. Results Four trials (N = 2499) were included. Patients received combination CDK4/6 inhibitor-endocrine therapy (N = 1441; ribociclib, [46.4%]; palbociclib, [30.8%]; or abemaciclib, [22.8%]) versus endocrine monotherapy (N = 1058). CDK4/6 inhibitor-endocrine therapy was associated with prolonged PFS compared with endocrine monotherapy (HR 0.56; 95% CI 0.50–0.62). In Asians (N = 492), PFS HR was 0.39 (95% CI 0.29–0.51, P < 0.0001). In non-Asians (N = 2007), PFS HR was 0.62 (95% CI 0.54–0.71, P < 0.0001). There was a significant treatment-by-ethnicity interaction (P = 0.002). Toxicity data by ethnic subgroup were only available from two trials (n = 1334) with no convincing evidence that the risk of toxicity between CDK4/6 inhibitor-endocrine therapy and endocrine monotherapy varied by ethnicity.Conclusion Adding CDK4/6 inhibitor to endocrine therapy prolongs PFS compared to endocrine therapy alone as first-line treatment in advanced breast cancer. The magnitude of PFS benefit is ethnicity-dependent but there is no interethnic dif- ferences in relative treatment-related toxicities. These findings may assist in the design and interpretation of trials, inform economic analyses, and stimulate pharmacogenomic research.
Introduction
Breast cancer is the most common malignancy and a lead- ing cause of cancer-related death in Asia-Pacific women [1]. Over half of all advanced breast cancers diagnosed in Asia are hormone receptor positive in post-menopausal women [2]. Endocrine blockade has been the cornerstone first-line therapy for these patients. However, clinical prac- tice is changing, based on recent evidence that combina- tion cyclin-dependent kinase 4/6 (CDK4/6) inhibitors and endocrine therapy further prolonged progression-free sur- vival (PFS) over endocrine monotherapy [3–6].In randomized trials of CDK4/6 inhibitors [3–6], Asians are under-represented, constituting only 8–30% of total study subjects. Interethnic pharmacogenomic variations can influence drug metabolism and impact on treatment efficacy as illustrated by differences in clinical outcomes with tamoxifen therapy for different ethnicities [7]. The impact of interethnic differences on the efficacy and toxic- ity of CDK4/6 inhibitors remains poorly understood.Investigation of ethnicity–treatment interactions is important to inform the interpretation of trial results and can provide valuable biological insights. Individual trials are neither designed nor powered to assess ethnic subgroup differences. We address this clinical need by performing a systematic review and literature-based meta-analysis of trials of CDK4/6 inhibitors.We searched PubMed, MEDLINE, and EMBASE up to January 2018 to identify randomized trials of combina- tion CDK4/6 inhibitor-endocrine therapy versus endocrine monotherapy as first-line treatment of advanced breast cancer. We searched conference proceedings of American Society of Clinical Oncology, European Society for Medi- cal Oncology, American Association of Cancer Research, and San Antonio Breast Cancer Symposium to identify unpublished studies and obtain updated data.
For each trial, we extracted PFS hazard ratio (HR) and 95% confidence interval (CI) of the overall population and Asian/non-Asian subgroups. For treatment-related toxici- ties, we extracted the number of adverse events (AEs), dose reduction due to AEs, and treatment interruptions.We used the fixed-effects inverse-variance-weighted method for pooling results to estimate the PFS benefit and the Mantel–Haenszel method to estimate the risk of treat- ment-related toxicities. For the ethnic subgroup analysis, we tested for treatment–ethnic interactions to assess differ- ences in relative treatment benefits/toxicity between Asian/ non-Asian subgroups. We used the χ2 Cochran Q test to detect heterogeneity across trials. Two authors (KL, CL) extracted the data independently and discrepancies were resolved by consensus.
Results
We identified four eligible trials (Fig. 1). All were blinded placebo-controlled trials (Table 1). The risk of bias was low for three trials [3–5] and unclear for an unpublished study [6]. Patients were randomized to receive combination CDK4/6 inhibitor-endocrine therapy (N = 1441; ribociclib, [46.4%]; palbociclib, [30.8%]; or abemaciclib, [22.8%]) ver- sus endocrine monotherapy (N = 1058). The pooled overall PFS HR was 0.56 (95% CI 0.50–0.62, P < 0.0001, heteroge-neity P = 0.99). In Asians (N = 492), PFS HR was 0.39 (95% CI 0.29–0.51, P < 0.0001). In non-Asians (N = 2007), PFS HR was 0.62 (95% CI 0.54–0.71, P < 0.0001). There was a statistically significant interaction between treatment effect on PFS and ethnicity (P = 0.002, Fig. 2).The most common AEs of combination therapy were neu- tropenia, infections, diarrhea, and nausea (Table 2; Fig. 3). Only two trials [3, 8] reported AEs rates, dose reduction, and treatment interruptions for Asian/non-Asian subgroups. Asians had higher rates of all grade neutropenia than non- Asians with combination (90.9% vs. 75.1%, P = 0.00001) and endocrine monotherapy (11.5% vs. 4.9%, P = 0.04) but there was no significant interethnic difference in relative risk (interaction P = 0.07). Asians had similar rates of all grade nausea as non-Asians on combination therapy (39.4% vs. 42.4%, P = 0.76) but lower rates than non-Asians on endocrine monotherapy (8.2% vs. 29.7%, P = 0.003), hence the relative risk of nausea varied by ethnicity (interaction P = 0.007). Asians had lower rates of all grade diarrhea than non-Asians on combination (15.2% vs. 32.1%, P = 0.003) and endocrine monotherapy (6.6% vs. 22.8%, P = 0.01, inter- action P = 0.35). There were no significant interethnic differ- ences in other examined toxicities. Asians had high rates of dose reduction (58.0%) and treatment interruptions (75.0%) due to AEs in the combination therapy group but there was no significant interethnic difference in the relative risks of these events (Table 3).
Discussion
In this meta-analysis, CDK4/6 inhibitor-endocrine therapy reduced the risk of disease progression or death by 44% compared to endocrine monotherapy. The pooled PFS HR for Asian and non-Asian were significantly different (0.39 vs. 0.62, interaction P = 0.002). There was, however, no convincing evidence that the risk of toxicity between CDK4/6 inhibitor-endocrine therapy and endocrine mono- therapy varied by ethnicity.This meta-analysis demonstrates consistency in PFS benefit across first-line trials overall and within ethnic subgroups with no significant heterogeneity. However, interethnic differences in PFS result were not observed in the second-line setting. PALOMA-3, [9] a second-line trial, compared fulvestrant with or without palbociclib reported no significant difference between Asians and non-Asians (PFS HR 0.49 vs. 0.45, interaction P = 0.83). Similar finding was reported for MONARCH-2, [10] another second-line study. The conflicting findings could be explained by different part- nering endocrine agents where aromatase inhibitors were used instead of fulvestrant. The patient populations were also different; none had chemotherapy for their advanced disease in the first-line trials, whereas 78% of patients in PALOMA-3 received chemotherapy.The high rates of neutropenia observed in first-line tri- als are also consistently reported in later line trials of CDK4/6 inhibitor [9, 11, 12]. PALOMA-3 trial reported pre-treatment absolute neutrophil count was 19% lower for Asians compared to non-Asians [9] and it remains unclear whether this would result in greater risk of neutropenia dur- ing CDK4/6 inhibitor therapy. In our meta-analysis, the rela- tive risk of neutropenia on combination versus endocrine monotherapy was not significantly different between Asians/ non-Asians (interaction P = 0.07).
Our analysis, however, could not quantify clinically significant toxicities, such as grade 4 neutropenia, as these results are not published in all trials by Asian/non-Asian subgroups. Importantly, our analy- sis showed no interethnic differences in relative treatment interruptions and dose reduction due to this and other AEs. Interethnic differences in drug exposure could poten- tially explain the finding of this meta-analysis. However, pharmacokinetic (PK) studies are conflicting and do not yet provide strong support for this hypothesis. In a phase 1 study (A5481032) of palbociclib, Japanese healthy sub- jects (N = 14) had mean drug concentration area under curve (AUC) and maximum drug concentration (Cmax) values of 30% and 35% higher, respectively, when compared with demographic-matched non-Asian subjects (N = 13) after single 125-mg dose. However, this finding was not con- sistently reproduced in subsequent studies. PALOMA-3 trial reported no significant difference in drug exposure for Asians from predominantly Taiwan and Japan (N = 105) ver- sus non-Asians (N = 416) [9]. Another phase 1 Chinese trial (N = 26) reported drug exposure similar to those obtained in Caucasian patients following the same dosing regimen [13]. In a phase I study (N = 17) of Japanese patients treated with ribociclib, mean AUC was 1.5–2 times greater than reported in studies of non-Asian populations [14]. However, the investigators noted the wide inter-individual variability limited conclusions about differences in drug metabolism for Asian versus non-Asian populations. These cumulative pharmacokinetic data from multiple trials across the three CDK 4/6 inhibitors do not provide sufficient evidence for dose adjustment based on Asian race.
Very little is known of the impact of cytochrome P450 polymorphism on CDK4/6 inhibitor metabolism. Palboci- clib undergoes hepatic metabolism primarily metabolized by CYP3A and sulfotransferase enzyme SULT2A1. Ribociclib also undergoes extensive hepatic metabolism, the major- ity of which is mediated by CYP3A4. CYP3A is also the enzyme responsible for the majority of the CYP-mediated metabolism of abemaciclib and its metabolite. Differences in the frequencies of different CYP3A alleles have been reported between Asians and Caucasians [15]. A single polymorphism of CYP3A4 could result in more than a three- fold difference in CYP3A4 enzyme expression between Cau- casians and Asians [16]. We hypothesize that interethnic difference in CYP3A4 polymorphism may account for the differences in treatment efficacy.
This meta-analysis has limitations. Ethnicity was self- reported with no standardized definitions across trials. Some trials defined Asian ethnicity based on country of residence or whereas other studies based on patient self- reporting. There is no clear definition of mixed race in all of the included studies. AEs, dose reduction, and treatment interruption data stratified by ethnicity subgroup were only available in two trials which limited our power to identify true ethnic differences. Finally, we regarded ribociclib, palbociclib, and abemaciclib as a single class of drug with equivalent therapeutic efficacy. All three agents, however, have some differences in mechanisms of actions and are also metabolized slightly differently as well.
Despite these limitations, the findings of this meta- analysis have important implications. Future CDK4/6 inhibitor trials should stratify patients based on ethnicity to improve estimation and interpretation of treatment ben- efits. Standardized definition of ethnicity is recommended. Differences in treatment efficacy impact cost-effective- ness and these findings also have important implica- tions for economic evaluations for reimbursement deci- sions for CDK4/6 inhibitors in different regions. Further ϮP value for the test of difference between Asian versus non-Asian subgroup treated with combination CDK4/6 inhibitor-endocrine therapy ϰP value for the test of difference between Asian versus non-Asian subgroup treated with endocrine monotherapy therapy #PALOMA-2 and MONARCH-3 trials report data for any type of infection; MONALEESA-2 Asian/non-Asian subgroup reports only upper res- piratory tract infections. Data were unavailable for MONALEESA-7 trial pharmacogenomic studies are required to investigate the interethnic differences in genetic polymorphisms of CYP3A4, CDK4/6 inhibitor PK, and clinical outcomes to potentially guide future clinical practice. This future work should also include development of objective genomic classifiers to define ethnicity given the potential impact of CDK inhibitor pharmacogenomics differences on treatment efficacy and toxicity.