An-Shun Zhang, Jiang-Xia Yin, Chang-Ming Song

1Department of pharmacy, Shouguang Hospital of Traditional Chinese Medicine, Shouguang 262700, China.2Department of Medical Oncology, Shouguang Hospital of Traditional Chinese Medicine, Shouguang 262700, China.

Abstract As a specific cyclin-dependent kinase 4/6 inhibitor, palbociclib improved the prognosis in patients with hormone receptor-positive and human epidermal growth factor receptor-2 negative breast cancer.Emerging data showed that palbociclib shed a new therapeutic regimen for breast cancers and plays an essential milestone in the development of anti-tumor drugs, especially for advanced breast cancer.In this mini review, we aimed to summarize the mechanism, clinical application, and side effects of palbociclib.

Keywords: palbociclib; advanced breast cancer; disease-free survival; adverse event

Background

Breast cancer is the most common solid malignancy in women, of them nearly 80% are hormone receptor-positive (HR+); and of them, more than 60% are HR+ and human epidermal growth factor receptor-2 negative (HER2-) [1].The endocrine therapy regimen, such as selective estrogen receptor (ER) modulators, selective ER down regulators, and aromatase inhibitors (AIs), is considered a standard regimen and improves survival outcomes in patients with HR+/HER2- breast cancer[2].The combination of endocrine therapy with cyclin-dependent kinase 4/6 (CDK4/6) inhibitor has further produced a huge leap in response to endocrine resistance of advanced breast cancer.

The emerging randomized clinical trials demonstrated that palbociclib, as the first CDK4/6 inhibitor, and endocrine therapy have considerably decreased breast cancer recurrence and mortality of breast cancer [2–7].Given the successful evidence of palbociclib for HR+/HER2- patients, palbociclib in combination with endocrine therapy has been approved as the preferred treatment for patients with estrogen receptor-positive (ER+), human epidermal growth factor receptor-2 (HER2) negative advanced breast cancer [8, 9].Here, we performed the mini review research of all previously published articles in PubMed or Google Scholar with the following keywords: “palbociclib”, “PD0332991”, and “CDK4/6 inhibitor” with limitations as to advanced or metastatic breast cancer.In the narrative review, we aim to summarize the mechanisms of palbociclib and the efficacy and adverse events of palbociclib.

The mechanism of palbociclib in breast cancer

CDK 4/6 regulates cell cycle transitions and mediates the transition from the G1 to S phase by targeting retinoblastoma (Rb) protein [10, 11].Rb plays its primary role through its effects on binging E2F and thereby inhibit G1/S transition [2, 12].Rb is regulated by phosphorylation, and only activated Rb can mediate cell proliferation [2].CDK4/6 forms a complex with cyclin D1 and then phosphorylates Rb [13].Palbociclib, as a member of the CDK4/6 inhibitor, interferes with the phosphorylation of Rb by inhibiting the binding of cyclin D, thereby inhibiting the proliferation of tumor cells, including breast cancer [13].

Palbociclib in combination with aromatase inhibitors

PALOMA-1 is the first randomized phase 2 study comparing the efficacy and safety of palbociclib plus letrozole versus placebo plus letrozole [14].One hundred sixty-five patients from 12 countries were randomly assigned to the palbociclib plus letrozole group (84 patients) and the letrozole group (81 patients).PALOMA-1 final results displayed that palbociclib combined with letrozole has a significantly improved progression-free survival (PFS) than letrozole alone in postmenopausal women with no prior treatment.Table 1 shows the detailed information about enrolled patients in trials.

Moreover, the phase 3 PALOMA-2 trial with randomized 2:1 was used to evaluate the findings of PALOMA-2.PALOMA-2 results confirmed palbociclib combined with letrozole has a significantly longer PFS than that with letrozole alone (HR = 0.58;P＜ 0.001), with a higher incidence of adverse events in the palbociclib group (9.7% versus 5.9% in the placebo group) [15].Palbociclib to letrozole maintains the health-related quality of life and has a better pain score than the placebo group [16].

Recently, a randomized, double-blind, phase 3 AMEERA-5 trial was ongoing, and 415 patients were enrolled to evaluate the efficacy and safety of amcenestrant in combination with palbociclib first-line therapy in advanced breast cancer with ER+/HER2- [17].

Palbociclib in combination with fulvestrant

PALOMA-3 was a phase 3 trial (fulvestrant plus palbociclib or placebo) focused on premenopausal women with hormone receptor-positive and HER2-negative metastatic breast cancer who de novo metastatic disease or relapsed within 12 months of adjuvant endocrine therapy [6].The PALOMA-3 at first analysis reported that the addition of palbociclib improved PFS from 4.6 months to 9.5 months [6].With 44.8 months of follow-up, the updated results showed that palbociclib combined with fulvestrant prolonged the overall survival than fulvestrant alone (HR = 0.81;P= 0.09) [7].

In addition, the double-blind, phase 2 FLIPPER trial with enrolled de novo metastatic breast cancer or relapsed after receiving adjuvant endocrine therapy ＞ 12 months showed that the 1-year PFS rate seemed to a benefit in palbociclib plus fulvestrant group versus placebo plus fulvestrant group (HR = 0.55,P= 0.064) [18].Also, the study reported results favoring this palbociclib plus fulvestrant over placebo plus fulvestrant with a statistically significant improvement in PFS [18].

Palbociclib plus fulvestrant in advanced breast cancer from a Real-world study clarified that it seems an effective treatment for advanced HR+/HER- breast cancer with a longer median PFS (7.43 months) and a better OS (24.70 months) [19].

Palbociclib versus chemotherapy

Palbociclib-based therapy is the preferred option for HR+ and HER2- metastatic breast cancer, but sometimes chemotherapy may be a better choice for aggressive breast cancer with a visceral crisis.Thus, it is also necessary for us to compare the therapeutic effect of chemotherapy or palbociclib-based therapy.KCSG-BR15-10 was a multicentre phase 2 trial focused on premenopausal women with HR-positive and HER2- breast cancer, with patients randomly assigned to receive either palbociclib plus exemestane or capecitabine.Additional ovarian function suppression was used in the palbociclib-based group.The palbociclib plus exemestane regimen significantly improved PFS (HR = 0.66;P= 0.02) compared with the capecitabine regimen [4].In a phase 3 randomized PEARL trial for HR+ and HER2- metastatic breast cancer patients resistant to AIs, palbociclib plus fulvestrant or exemestane are not superior to capecitabine in PFS; however, therapeutic benefits and superiority in safety and tolerance [20]

Palbociclib, in combination with immunological therapy

One phase I/II trial showed that palbociclib combined with pembrolizumab and letrozole is well tolerated in patients with HR+ and HER2- metastatic breast cancer [21].Twenty patients were analyzed in the study, such as four patients in cohort 1 and 16 patients in cohort 2.The Clinical benefit rate was 100% in cohort 1 and 88% in cohort 2, and the object response rate was 50% in cohort 1 and 56% in cohort 2.

Adverse event of palbociclib

With the absolute improvement of the palbociclib-based regimen in PFS, palbociclib-related side effects also should be brought to our attention.The common hematologic toxicity is neutropenia, leukopenia, anemia, and lymphopenia, and non-hematologic toxicity is thrombocytopenia, mucositis, diarrhea, abnormal liver enzymes, fatigue, respiratory infection, and back pain, and so on.Past studies revealed that palbociclib is mainly mediated by CYP3A enzyme and undergoes hepatic metabolism in vivo; hence, strong the CYP3A inhibitors should be avoided to reduce its exposure [22].Nevertheless, previous randomized phase 3 studies have shown that the palbociclib was well tolerated and has controllable side effects by dose modification and supportive treatment [6, 16, 20, 21, 23].The detailed adverse events on palbociclib are listed in Table 2.

Table 1 The trials of palbociclib in advanced breast cancer

Table 2 Grade 3+ adverse event in the palbociclib group (%)

Conclusion

The FDA firstly approved the palbociclib plus letrozole for the treatment of postmenopausal women with HR+ and HER2- metastatic breast cancer in 2015 based on the PALOMA-1 trial; and then the palbociclib combined with fulvestrant was approved in 2016 based on PALOMA-2 trial.Palbociclib combined with endocrine therapy has been standard therapy for hormone receptor-positive and HER2- advanced breast cancer, even the patients with visceral metastases [9,

24].On the other hand, clinicians are concerned about treatment options for patients with HR low expression in HR+; and whether the patients with HR low expression have the same therapeutic effect as the patients with HR+/HER2- remains unclear.Some ongoing clinical trials will help to answer the critical question.

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