FDA information also cautions against consuming grapefruit products while taking palbociclib, in order to avoid negative interactions.

At the time of publication, there was insufficient data on overall survival, and a final analysis is planned after a total of 390 deaths occur per protocol and in agreement with regulatory agencies.

[14] The drug was approved for use in the European Union in November 2016 as a treatment for hormone receptor (HR) positive, human epidermal growth factor receptor 2 (HER2) negative locally advanced or metastatic breast cancer, either in combination with an aromatase inhibitor or, for women who have received prior endocrine therapy, in combination with fulvestrant.

[17] More than 10% of patients also experience side effects such as fatigue, nausea, diarrhea, respiratory infection, headache, thrombocytopenia, vomiting, and decreased appetite.

Overexpression of the transcription factor E2F2 is capable of promoting resistance to CDK4/6 inhibition more than just loss of Rb alone (the direct downstream target of CDK4/6).

Because CDK4/6 inhibition acts directly downstream of the endocrine therapy targets, cross-therapy resistance could possibly develop as a result of patient progression on hormone-therapy.

For example, deficiencies in mismatch repair caused by the MutL mutation in ER+ breast cancer evades CHK2-mediated inhibition of CDK4, thereby leading to endocrine resistance.

Researchers at the Dana Farber Institute found that breast cancer cells that developed resistance to palbociclib were resensitized to the drug after a seven-day "treatment holiday".

[24] Scientists linked the initial development of resistance to an increase in expression of CDK6 (but not CDK4, the other target of palbociclib), with the specific mechanism of CDK6 upregulation originating from suppression of the TGF-β pathway via the miR-432-5p microRNA.

Previous research estimates that breast cancer cells show adaptation against palbociclib as early as 72 hours post-treatment.

[26] In the phase II PALOMA-1 trial reported at the April 2014 annual meeting of the American Association for Cancer Research, the addition of palbociclib to letrozole was shown to significantly slow the progression of advanced cancer (median progression-free survival increased from 10.2 months to 20.2 months), but was not shown to have a statistically significant effect on increasing patients' overall survival times.

The results indicate that, when used in combination with post-surgery endocrine therapy, it "is unlikely to show a statistically significant improvement in the primary endpoint of invasive disease-free survival (iDFS).

According to the NIH National Cancer Institute there are currently 39 active clinical trials testing palbociclib on its own or in combination with other medications.

The trial has also demonstrated greater than a year's improved median progression free survival for patients on the combined therapy (as compared to letrozole on its own).

PALOMA-2 median patient follow-up time now exceeds three years, making it the longest traceable data for phase III study of a CDK4/6 inhibitor.

In September 2017, abemaciclib, another selective CDK4/6 inhibitor owned and manufactured by Eli Lilly, was approved for HR-positive, HER2-negative advanced metastatic breast cancer both in combination with fulvestrant and as a monotherapy.

[34] G1 Therapeutics[35] also has a CDK4/6 inhibitor, trilaciclib, which is up for FDA approval (target decision date of February 15, 2021) for use in small cell lung cancer.