Gondal, Farva R.

e12545 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.

Background: Four large RCTs (ASSURE, S-TARC, PROTECT, ATLAS) tested adjuvant VEGF-TKI therapy in high risk RCC. The results were variable for efficacy and there were concerns for increased toxicity and decline in quality of life (QoL). We performed an updated meta-analysis including results of ATLAS trial to asses a risk-benefit for adjuvant post-operative treatments in high risk RCC patients by assessing reported disease-free survival (DFS), overall survival (OS), and toxicity endpoints. Methods: Literature search was done using Medline, CENTRAL, and Embase. The DerSimonian and Laird random effects model was used to pool estimates for DFS, OS, and common side effects across the 4 trials. A subgroup analysis was performed for sunitinib alone because of its FDA approval. Heterogeneity was assessed with Cochrane Q statistic and was quantified with I2 test. Risk for bias was assessed using the Cochrane Collaboration’s tool. Results: The 4 RCTs included 4,820 patients. Adjuvant therapy with TKIs yielded no significant improvement in DFS or OS as compared to placebo (DFS HR=0.916; 95% CI, 0.832–1.009 and OS HR=1.09; 95% CI, 0.886–1.150). Separate analysis of DFS in sunitinib vs placebo did not show any benefit (2 studies, N=1,909; HR=0.90; 95% CI, 0.67–1.19). Use of TKIs was associated with significantly increased risk of drug toxicity. Increased risk of grade 3 or 4 adverse events (RR=5.110; 95% CI, 3.765–6.935), diarrhea (RR=10.725; 95% CI, 4.672–24.622), fatigue (RR=3.310; 95% CI, 1.879–5.829), hypertension (RR=4.274; 95% CI, 3.452–5.292) and palmar/plantar dysesthesia (RR=20.53; 95% CI, 9.006–46.801) was observed. There was no statistically significant heterogeneity amongst included trials. QoL endpoints were inconsistently reported. Risk of bias was low. Conclusions: This pooled analysis provides further evidence that there is no OS or DFS benefit associated with adjuvant TKI treatment. There was a significantly increased risk of grade 3 or 4 toxicity in greater than half of the patient population leading to decline in QoL during TKI therapy. Carefully selected very high-risk patients who can tolerate these agents without dose modifications may benefit from adjuvant TKI approach.