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Current insights: CDK4&6 inhibitors as a therapeutic option for HR+/HER2− breast cancer
Dr Fatima Cardoso considers the clinical data on the three CDK4&6 inhibitors, abemaciclib, palbociclib, and ribociclib. First to reach the clinic was palbociclib, investigated in the phase 2 PALOMA 1 trial. Patients with ER+/HER2− breast cancer, 45–50% of whom had visceral disease, received letrozole alone or with palbociclib. Addition of palbociclib extended the median PFS by 10 months, but an attempt to identify biomarkers failed. Common adverse events were neutropenia and leukopenia, some thrombocytopenia and anaemia, and fatigue. These findings were confirmed in the phase 3 trial PALOMA 2 and led to the ABC3 recommendation for first-line use of palbociclib in in postmenopausal women. Palbociclib, with fulvestrant, also improved PFS and QoL in women with refractory HR+/HER2− tumours in the PALOMA 3 trial. Overall survival results are awaited. Palbociclib is being investigated in other settings and in comparison with capecitabine. The second CDK4&6 inhibitor to reach phase 3, ribociclib, is being tested in the MONALEESA trials, one of which is dedicated to premenopausal women. Single-agent activity of ribociclib has been confirmed in aromatase-inhibitor-resistant advanced breast cancer; ribociclib is also being evaluated in triple combinations including PI3K inhibitors. Abemaciclib has also shown single-agent activity and, importantly, durable responses in patients with luminal breast cancer (MONARCH trials). The safety profiles of the three drugs differ. It remains to be seen how these drugs compare with other agents and how they will best be used with other agents. Biomarkers remain undefined, and cost implications remain unknown.