Background: CDK4 and CDK6 are cyclin-dependent kinases that control transition between G1 and S phases of the cell cycle, hence controlling cell cycle progression by reversible combination with cyclin D1. In cancer cell, CDK4/6 activity is overexpressed, which can lead to amplification or overexpression of the genes encoding for CDK 4/6 or the cyclin D. Additionally, loss of endogenous INK4 inhibitors can also lead to over activity of CDK4 and CDK6. We undertook a meta-analysis of randomized controlled trials (RCT) to determine the risk of gastrointestinal (GI) and hepatic toxicities associated with CDK 4/6 inhibitors. Methods: We conducted a comprehensive literature search using MEDLINE, EMBASE databases, and meeting abstracts from inception through September 2018. In our analysis, we incorporated RCTs that mention GI toxicities and elevation of aspartate aminotransferase (AST) or alanine aminotransferase (ALT) as adverse effects. Mantel-Haenszel (MH) method was used to calculate the estimated pooled risk ratio (RR) with 95% CI. Random effects model was applied. Results: A total of 4,557 patients with advanced breast cancer from 7 phase III and 1 phase II RCTs were eligible. The study arms used were palbociclib/ribociclib/abemaciclib or placebo in combination with letrozole or anastrozole or fulvestrant or other hormonal agents. The RR of all-grade side effects were as follows: diarrhea, 1.691 (95% CI: 1.220–2.345; P=.002); nausea, 1.632 (95% CI: 1.447–1.840; P<.001); vomiting, 1.684 (95% CI: 1.256–2.259, P=.001); stomatitis, 2.160 (95% CI: 1.332–3.503; P=.002); elevated AST, 1.832 (95% CI: 1.312–2.558; P<.001); and elevated ALT, 2.150 (95% CI: 1.649–2.803; P<.001). The RR of high-grade side effects were as follows: diarrhea, 2.592 (95% CI: 0.853–7.877; P=.093); nausea, 1.326 (95% CI: 0.589–2.988; P=.496); vomiting, 1.089 (95% CI: 0.479–2.476; P=.839); stomatitis, 2.097 (95% CI: 0.502–0.753; P=.310); elevated AST, 2.274 (95% CI: 1.173–4.410; P=.015); and elevated ALT, 3.988 (95% CI: 2.387–6.663; P<.001). Conclusions: Our study demonstrated that the risk of developing all grade GI toxicities and all grades of hepatic side effects including grade 3 and 4, was high in CDK 4/6 inhibitors group, compared to control arm, and prompt intervention with good supportive care is required.
Anita Sultan, Sriman Swarup, Somedeb Ball, Miguel Quirch, Meily Arevalo, Yin M. Myat, Ye Aung, Myo H. Zaw and Kyaw Z. Thein
Meily Arevalo, Myo H. Zaw, Anita Sultan, Sriman Swarup, Nay N. Yee, Wai L. Thein, Myet M. Zin, Nusrat Jahan and Kyaw Z. Thein
Background: Ibrutinib targets Bruton’s tyrosine kinase, a kinase involved in signaling of B-cell and chemokine receptors, which are implicated in the pathogenesis of hematologic malignancies. Ibrutinib has been shown to improve survival in hematologic malignancies, and yet the tolerability has not been elucidated. We undertook systematic review and pooled analysis of randomized controlled trials (RTCs) to determine the risk of gastrointestinal toxicities and the rate of treatment discontinuation due to adverse events. Methods: We performed a comprehensive literature search using MEDLINE, EMBASE databases and meeting abstracts through September 2018. Phase 3 RCTs that mention gastrointestinal toxicities and the rate of treatment discontinuation due to adverse events were incorporated in the analysis. Mantel-Haenszel method was used to calculate the estimated pooled risk ratio with 95% CI. Random effects model was applied. Results: 6 phase III RCTs with a total of 1,811 patients with chronic lymphocytic leukemia/small lymphocytic lymphoma, mantle cell lymphoma, and Waldenstrom’s macroglobulinemia were included. Studies comparing ibrutinib vs ofatumumab, ibrutinib vs chlorambucil, ibrutinib + bendamustine + rituximab vs placebo + bendamustine + rituximab, ibrutinib vs temsirolimus, and ibrutinib vs rituximab were included in the analysis. The incidence of treatment discontinuation due to adverse events was 9.30% in the ibrutinib group vs 13.13% in the control arm. The relative risk (RR) for treatment discontinuation was 0.740 (95% CI: 0.385–1.423; P=.367). The pooled RR of all-grade side effects were as follows: diarrhea, 1.955 (95% CI: 1.304–2.933; P=.001); nausea, 1.038 (95% CI: 0.702–1.534; P=.852); vomiting, 1.048 (95% CI: 0.547–2.007; P=.888); and stomatitis, 1.262 (95% CI: 0.112–14.173; P=.850). The RR of high-grade adverse effects were as follows: diarrhea, 1.749 (95% CI: 0.866–3.530; P=.119); nausea, 2.237 (95% CI: 0.478–10.471; P=.306); vomiting, 0.429 (95% CI: 0.111–1.659; P=.220); and stomatitis, 0.309 (95% CI: 0.028–3.440; P=.340). Conclusion: Our study demonstrated that patients on ibrutinib arm noted increased risk of all-grade diarrhea. Nevertheless, other GI toxicities as well as treatment discontinuation due to adverse events were not statistically significant in the ibrutinib group compared with the control arm.