CDK inhibitors (Cyclin-dependent kinase)

They inhibit the proliferation of cancer cells by arresting them in the G1 phase of the cell cycle.

 

This class of inhibitors is largely cytostatic rather than cytocidal, meaning that it blocks cell proliferation rather than killing the cells. 

These inhibitors are used as frontline medications for patients with advanced, HR+/HER2- breast cancers.

CDK 4/6 inhibitors are effective in de novo or recurrent metastatic breast cancer, in primary or secondary endocrine resistance, and post menopausal or pre-menopausal women, the latter with a luteinizing hormone releasing hormone, and in men within LH-RH agonist.

Numerous studies show a significant improvement in progression free survival with first line or second line use of palbociclib, riboclib or abemaciclib in combination with endocrine therapy (an aromatic inhibitor or fulvestrant), as compared with endocrine therapy alone and overall survival benefit with first line use of either ribociclib or absmaciclib in combination with endocrine therapy.

Endocrine therapy plus CDK4/6 inhibition yield similar or better efficacy versus chemotherapy and it is associated with less toxicity.  making it the preferred treatment unless a patient has imminent organ failure.

Palbociclib and  ribociclib must be combined with endocrine therapy to demonstrate efficacy in breast cancer, but abemacoclib has demonstrated limited single agent efficacy.

For patients who do not relapse on an aromatase  inhibitor, or within 12 months of stopping adjuvant AI, a CD4/6 inhibitor in combination with an AI is advised.

CDK4/6 inhibitors plus endocrine therapy or aromatase inhibitor therapy combinations are recommended regimens for patients with progression after completion of adjuvant 7endocrine therapy, or for patients with who present with de novo metastatic breast cancer.

CDK/6 inhibitors plus fulvestrant show similar increase in progressive free survival in recurrent ER+ breast cancer.

Highly efficacious in the treatment of metastatic hormone receptor positive breast cancers, most of which depend on the cyclin D-CDK 4/6-retinoblastoma protein axis for sustain cancer cell proliferation.

CDKs 4 and 6 are members of a family of kinase is involved in cell division and several other cellular metabolic processes.

Comparisons of effectiveness of the various CDK4/6 inhibitors is not possible, and toxicity profiles are only slightly different.

In patients with estrogen receptor positive breast cancers they are part of the chain of effector molecules linking the estrogen receptor with the cell cycle.

Estrogen stimulates expression of cycling D1, facilitating activation of CDK 4 and 6, retinoblastoma phosphorylation, subsequent release of E2F and cell proliferation.

All CDK 4/6 inhibitors exert their antitumor effect by blocking cell cycle progression through the inhibition of the cyclin D-CDK 4/6 complex, which in turn suppresses the activation of the downstream RB-E2 F pathway.

Inhibition of CDK 4 and 6 leads to cell cycle arrest, which in turn can lead to initiation of apoptosis or cell senescence.

Have become the standard of care for the initial treatment of advanced, hormone receptor positive breast cancer.

Efficacy of the 3 CDK/6 inhibitors appears to be similar.

Palbocyclib has comparable potency against cyclin D1/CDK4 and cyclin D2/CDK6, Abemaciclib and ribociclib have greater potency against CDK4 than CDK6

Abemaciclib also inhibits multiple other closely related kinases, including CDK1CDK2 and CDK5

CDK4/6 approvals were based on observed improvements in progression-free survival (PFS), and also overall survival across a series of clinical trials conducted as part of the PALOMA, MONALEESA, and MONARCH families of studies, including evidence of demonstrable activity in younger women with prior exposure to palliative chemotherapy and with visceral disease.

 

No specific subsets of patients with advanced disease who do not benefit from a CDK4/6 inhibitor.

 

Biomarkers that are used to predict drug activity or resistance include an intact retinoblastoma gene and estrogen receptor expression.

 

There are small differences in the toxicity profile, dosing schedule, clinician familiarity in CDK4/6 inhibitors.

 

The monarchE phase III study in which patients with high-risk early-stage breast cancer were randomly assigned to standard adjuvant endocrine therapy, with or without abemaciclib 150 mg twice daily for 2 years: there was clear evidence of an improved 2-year invasive disease-free survival (IDFS) favoring the abemaciclib arm.

 

The observed absolute invasive disease-free survival  improvement of 3.5% was statistically significant and is clinically meaningful.

 

The monarchE purposefully enrolled study participants with very-high-risk disease. 

 

The eligibility criteria threshold required a high anatomic risk (≥ 4 pathologic positive axillary lymph nodes or 1-3 positive lymph nodes if tumor ≥ 5 cm) or a mix of high anatomic and biologic risk (1-3 positive lymph nodes with tumor grade 3 or with centrally assessed Ki67 immunohistochemistry staining in ≥ 20% of tumor cells). 

 

Three-quarters of participants had stage III disease.

 

Approximately 12% had stage IIa disease.

 

Approximately 60% of participants had N2 disease, and approximately 40% had tumors that were high grade or had a high Ki67. 

 

More than 95% of participants received adjuvant chemotherapy and radiation therapy.

 

Approximately 45% of monarchE participants were premenopausal. 

 

Approximately half of them also received some form of ovarian suppression added to tamoxifen or to an aromatase inhibitor.

 

Approximately 17% discontinued abemaciclib, and approximately 6% of patients stopped both abemaciclib and endocrine therapy. 

 

Venous thromboembolic events and interstitial lung disease were observed in the abemaciclib arm at a 2.5% frequency each. 

 

PALLAS randomly assigned approximately 5,800 to a 2 year open-label palbociclib added to endocrine therapy did not improve invasive disease free survival compared with Edgeman endocrine therapy alone.

 

The PENELOPE-B study is focused on a specific group of patients with HR-positive/HER2-negative disease and residual disease at surgery after neoadjuvant chemotherapy who received 1 year of postneoadjuvant palbociclib or placebo: results pending.

Adjuvant trials of cyclin 4,6 inhibitors and endocrine therapy have shown longer disease free survival with these treatment combinations, than adjuvant and endocrine therapy alone (NATALEE TRIAL, monarchE trial).

 

Ongoing neoadjuvant trials are addressing chemotherapy de-escalation questions using survival as the primary objective.

Major phase 3 clinical trials have consistently demonstrated improved progression free survival with the use of CDK inhibitors alone or in combination with aromatase inhibitors or fulvestrant.

CDK inhibitors are generally well tolerated with major adverse effects including: neutropenia, fatigue, and diarrhea.

When CDK inhibitors become resistant, patients have worse prognosis, indicating that new molecular alterations in tumor cells limit the effectiveness of subsequent treatments.

A trial with ribociclib plus endocrine therapy versus endocrine therapy alone among patients with ER receptor positive, HER2 negative breast cancer showed significantly longer overall survival (MONALEESMA-7).

Abemaciclib exhibits unique therapeutic activity that could help inform the design of better treatment strategies, including optimized combination therapies and circumventing drug resistance.

Abemaciclib may unexpectedly work in patients who are not responsive to other drugs in the class.

Of CDK inhibitors only abemaciclib causes significant cancer cell death at high doses, , suggesting the drug may be affecting proteins other than only CDK4/6.

Palbociclib and ribociclib had minimal effects on cell death even when administered at higher doses.

First line therapy with ribociclib plus letrozole shows significant overall survival benefit as compared with placebo plus letrozole in patients with hormone receptor positive HER2  negative advanced breast cancer: median over survival overall survival was more than 12 months longer with ribociclib than with placebo.

CDK inhibitors in combination with endocrine therapy have been improved in first line and second line treatments for post menopausal ERpositive, ERBB2 negative metastatic breast cancer.

((Trilaciclib))can reduce chemotherapy induced myelosuppression.

It is no longer acceptable to assume that patients with advanced ER positive breast cancer should receive chemotherapy in early lines of therapy, even those with a significant visceral disease, and maybe even not for those with visceral crises.

All three approved CDK/6 inhibitors cause neutropenia, although it is more frequent and higher grade with palbociclib and ribociclib overall.

Ribociclib and abemacyclib plus endocrine therapy have been shown to improve overall survival in metastatic HR positive ERBB2 negative metastatic breast cancer.

The incidence of neutropenic fever is less than 2% with CDK inhibitors.

Abemaciclib has more frequent and higher grade diarrhea than the other two drugs.