The mechanism of action of palbociclib and similar drugs is by inhibition of CDK CD4 leading to reduction in phosphorylation of the Rb protein. There is a synergistic interaction whereby doing this improves endocrine sensitivity.
What side effects might this lead to?
It’s uncertain exactly how it leads to side effects but the same mechanism of action will apply in the bone marrow. The main side effect of this class of drugs is neutropenia and that’s probably due to quiescence of progenitor cells in the bone marrow rather than destruction of peripheral cells. So the mechanism is quite different to chemotherapy.
What other side effects are most commonly reported?
The side effects that are reported are uncommon; we find neutropenia by checking the blood count frequently. The incidence of febrile neutropenia which might be a reported side effect is around 1%. There is a slight increase in the risk of diarrhoea which is readily manageable, a slight increase in minor infective symptoms such as colds, slightly runny noses, but those are not things that lead to dose adjustment. So really the drug is well tolerated and in clinical trials quality of life is improved on these drugs rather than interfered with.
The trial designs have gone through the classical trial design route with phase I to establish safety and then phase II and then phase III. So initially these drugs proved their efficacy in second line metastatic breast cancer in combination with, for example, fulvestrant. Then the first line trials were in post-menopausal women in combination with an aromatase inhibitor. The endpoint of the trials has been progression free survival and both in the second line and first line setting the addition of palbociclib to a standard endocrine treatment nearly doubles progression free survival which is a very meaningful endpoint for patients.
Is there anything doctors and nurses need to be made aware of in the management of these adverse events?
The things that doctors and nurses need to be aware of is to follow the recommended protocol by checking the blood count day 1, day 14, of the first two cycles to establish the correct dose for an individual patient and also to follow the dose adjustment pattern. The other important thing to be aware of is these drugs can be interfered with by drugs that interfere with the CP3 pathway, either inhibitors of CP3 or inducers of CP3. So you need to take a very careful concomitant drug history to make sure that the patient isn’t on a drug that might increase the exposure to palbociclib or indeed reduce it. Out with the drugs they have to avoid grapefruit juice, which a lot of people like, and St John’s Wort, which a lot of people take. So you need to be quite careful about prescribed other drugs and non-prescribed substances.
