CDK4/6 inhibitors in advanced hormone receptor-positive/HER2-negative breast cancer: A network meta-analysis (NMA) of randomized controlled trials (RCTs).

person Muhammad Husnain University of Miami/Sylvester Cancer Center, Miami, FL info_outline Muhammad Husnain, Irbaz Bin Riaz, Farva R. Gondal, Saad Malik, Qurat Ul Ain Riaz Sipra, Ammad Raina, Mahnoor Islam, Gilberto Lopes

Authors person Muhammad Husnain University of Miami/Sylvester Cancer Center, Miami, FL info_outline Muhammad Husnain, Irbaz Bin Riaz, Farva R. Gondal, Saad Malik, Qurat Ul Ain Riaz Sipra, Ammad Raina, Mahnoor Islam, Gilberto Lopes Organizations University of Miami/Sylvester Cancer Center, Miami, FL, Mayo Clinic, Rochester, MN, University of Miami, Miami, FL, University of Arizona, Tuscon, AZ, BUMC, Tucson, AZ, Midwestern University, Sierra Vista, AZ, Dow University of Health Sciences, Karachi, Pakistan, University of Miami Health System, Miami, FL Abstract Disclosures Research Funding Other Background: Palbociclib(P), Ribociclib(R) and Abemaciclib(A) in combination with Endocrine therapy (ET) have demonstrated progression free survival (PFS) in patients with metastatic hormone receptor positive, HER2-negative breast cancer as compared to ET alone. In the absence of head to head clinical trials and to provide clinical guidance, we performed an indirect comparison for P, R and A using network Meta-Analysis (NMA). Methods: MEDLINE, EMBASE and the Cochrane Library were searched to identify RCTs comparing P+ET, R+ET, A+ ET vs ET alone. NMA for PFS and toxicity endpoints was conducted using a multivariate random-effects meta-regression, using a consistency model, as described by White and colleagues. We used a frequentist approach and provided a point estimate from the network and a 95% CI from the frequency distribution of the estimate. We also estimated the relative ranking of the different treatments for each outcome using the distribution of the ranking probabilities and the surface under the cumulative ranking curves (SUCRA). Risk of bias was assessed using Cochrane Collaboration tool. Results: 8 RCTs were identified including 4580 patients. Risk of bias was low. 5 RCTs tested CDK 4/6 inhibitors in endocrine naive and 2 in the refractory setting, while MONALESSA-3 included patients both with endocrine naive and endocrine resistant disease. In the endocrine naïve patients, PFS for P was similar when compared indirectly with R (HR, 0.95, 95% CI 0.67-1.35) or A (HR, 1.00, 95% CI 0.62-1.61). Similarly, indirect comparison between R vs A did not show any statistical significant (HR, 0.95, 95% CI 0.62-1.45). In endocrine refractory patients, P showed no difference when compared indirectly to A (HR 1.12, 95% CI 0.67-1.87) or R (HR 0.98, 95% CI 0.52-1.86). R vs A did not show any statistically significant PFS either (HR, 1.14, 95% CI 1.61-4.51). P was ranked first in terms of PFS in frontline setting (SUCRA of 70.5) while R ranked first in the refractory setting (SUCRA of 39.5). QT prolongation was reported for R only. P caused more neutropenia while A caused more fatigue, anemia and diarrhea, although the results were not statistically significant. Conclusions: The efficacy of using either palbociclib, ribociclib or abemaciclib in combination with ET was similar in terms of PFS in either endocrine naïve or resistant disease. Palbociclib causes more neutropenia, abemaciclib causes more fatigue, anemia and diarrhea while ribociclib causes QT prolongation.