*3.1.1. Palbociclib*

Palbociclib is a first-in-class CDK4/6 inhibitor [27]. Based on the impressive PFS found in the phase 2 study PALOMA-1 [28], palbociclib was granted accelerated approval in 2015 by the Food and Drug Administration (FDA) for treatment of HR+ve/HER2−ve MBC in the first line setting.

## *3.1.1.1. Key results of phase 3 PALOMA studies*

PALOMA-2, is a double-blind, placebo-controlled, randomized phase 3 study of palbociclib plus letrozole in women with HR+ve/HER2−ve MBC patients who had no prior treatment for advanced disease [29]. Patients were randomized to receive palbociclib plus letrozole or placebo plus letrozole. The primary end point was PFS. Secondary end points included OS, objective response rate (ORR), clinical benefit response (CBR) and safety. The study recruited 666 women within 17 months. The primary endpoint was met – the addition of palbociclib to letrozole, as compared with placebo-letrozole, increased the median PFS from 14.5 months (95% confidence interval [CI], 12.9–17.1) to 24.8 months (95% CI, 22.1 to not estimable) (hazard ratio [HR] 0.58, 95% CI, 0.46–0.72; p < 0.001). Subgroup analyses of PFS confirmed a consistent benefit across all subgroups evaluated including different race, prior disease-free survival, visceral involvement, prior hormonal therapy, the type of recent hormonal therapy, or prior chemotherapy (HR ranges, 0.35–0.67). The ORR for all randomly assigned patients in palbociclib-letrozole group versus placebo-letrozole group was 42.1% (95% CI, 37.5–46.9) and 34.7% (95% CI, 28.4–41.3) (odds ratio 1.4, 95% CI, 0.98–2.01; p = 0.06). CBR among all patients randomized was 84.9% (95% CI, 81.2–88.1) for palbociclib-letrozole group and 70.3% (95% CI, 63.8–76.2) for placebo-letrozole group (odds ratio 2.39 (95% CI, 1.58–3.59; p < 0.0010). The most frequent grade 3 and 4 adverse event (AE) in the palbociclib-letrozole group was neutropenia (66%), but febrile neutropenia occurred in 1.8% of patients only. Other common AE included fatigue (37%), nausea (35%), arthralgia (33%), alopecia (33%) and diarrhea (26%) and all these were mild.

PALAMO-3 is another indication-defining phase 3 study of palbociclib [30]. Patients with HR+ve/HER2−ve HER2-negative MBC who had relapsed or progressed during prior endocrine therapy were randomized to receive fulvestrant with placebo or fulvestrant with palbociclib. A total of 521 patients were randomized. The median PFS was 9.2 and 3.8 months in the fulvestrant-palbociclib and fulvestrant-placebo groups respectively (95% CI, 2.5–5.5) (HR 0.42, 95% CI, 0.32–0.56; p < 0.001). ORR was 10.4% with fulvestrant-palbociclib and 6.3% with fulvestrant-placebo, and the CBR was 34% with fulvestrant-palbociclib and 19% with fulvestrantplacebo. In the fulvestrant-palbociclib group, grade 3 or 4 neutropenia was found in 62%. Other common AEs were fatigue (38%), nausea (29%), anemia (26%), and headache (21%).

The results of PALOMA-2 echo those of PALOMA-1 that led to FDA approval. PALOMA-1 differs from PALOMA-2, besides being a phase 2 trial, in that it adopted a 1:1 randomization. There were also small differences in the subgroup analysis, such as inclusion of the newly diagnosed metastatic disease subgroup. Nevertheless, both studies showed significant survival benefit of palbociclib and similar toxicity profiles.
