Clinical trialPhase 3Breast cancer

Palbociclib and Letrozole in Advanced Breast Cancer

N Engl J Med · 2016666 patients

Finn RS, Martin M, Rugo HS, Jones S, Im SA, Gelmon K, et al. N Engl J Med. 2016. 375:1925-1936

Study type: Clinical trial
Study name: PALOMA-2
Phase: Phase 3
Design: Randomised, double-blind trial with 2:1 randomisation (palbociclib plus letrozole versus placebo plus letrozole)
Sample size: 666 patients
Source: N Engl J Med · 2016
Trial registration: NCT01740427

In plain words

This study looked at postmenopausal women with advanced hormone-sensitive breast cancer (ER-positive and HER2-negative) who had not yet had any treatment for their advanced disease. Adding palbociclib to letrozole kept the disease from progressing for longer on average (about 24.8 months vs 14.5 months). On the other hand, a drop in white blood cells (especially neutrophils) was much more common in the palbociclib group and requires regular blood tests.

Key results

24.8 months vs 14.5 months

Median PFS (median progression-free survival)

Palbociclib–letrozole (95% CI: 22.1 to not estimable) vs placebo–letrozole (95% CI: 12.9 to 17.1)

0.58

Hazard ratio for disease progression or death

95% CI: 0.46 to 0.72; P<0.001

Drugs in this study:Abemaciclib (Verzenio)Fulvestrant (Faslodex)Letrozole (Femara)Palbociclib (Ibrance)Anastrozole (Arimidex)Ribociclib (Kisqali)

Dose and schedule cards

Hormone therapy + CDK4/6 inhibitor (PALOMA-2, MONALEESA-2, MONARCH 3; after progression: PALOMA-3)

Advanced HR-positive/HER2-negative disease; first-line with an aromatase inhibitor, or with fulvestrant after prior hormone therapyOn the page “Breast cancer” · Advanced hormone receptor-positive / HER2-negative disease

Advanced HR-positive/HER2-negative disease; first-line with an aromatase inhibitor, or with fulvestrant after prior hormone therapy

Drug	Dose	Route	Schedule
One of three drugs
Palbociclib	125 mg once daily	Oral	Days 1–21
Ribociclib	600 mg once daily	Oral	Days 1–21
Abemaciclib	150 mg twice daily	Oral	Continuous
Combined with
Letrozole (or anastrozole 1 mg)	2.5 mg once daily	Oral	Continuous
Or combined with
Fulvestrant	500 mg (two 5-mL injections, one in each buttock)	IM, slowly	Days 1, 15 and 29, then monthly

Cycle length: Palbociclib and ribociclib: every 28 days; abemaciclib continuous
Duration: Until progression or unacceptable toxicity

Ribociclib: reduce to 400 mg and then 200 mg. Abemaciclib: monotherapy 200 mg twice daily.

On the page “Breast cancer” · Advanced hormone receptor-positive / HER2-negative disease

Doses follow the trial protocol, guideline or official drug label (source given in the notes of each regimen). Before prescribing, check blood counts, renal and hepatic function, drug interactions and the patient’s condition, and adjust the dose according to the drug label.

Treatment arms and regimens

1Palbociclib plus letrozole

Palbociclib 125 mg orally once daily on days 1 to 21 of each 28-day cycle (7 days off), with letrozole 2.5 mg orally once daily continuously; until progression, symptomatic deterioration, unacceptable toxicity, death or withdrawal (two thirds of patients, 2:1 ratio).

2Placebo plus letrozole

Placebo once daily on days 1 to 21 every 28 days, with letrozole 2.5 mg daily continuously.

Source of the regimen details: ClinicalTrials.gov NCT01740427 and the FDA label for Ibrance (DailyMed, section 14)

Doses are given for the information of specialists, as in this study’s protocol, and are not a prescription. Every drug must be prescribed by the treating physician for the individual patient.

Study population

Postmenopausal women with oestrogen receptor (ER)-positive, HER2-negative advanced breast cancer who had not received previous treatment for advanced disease.

Endpoints

Primary endpoint: investigator-assessed progression-free survival (PFS).

Secondary endpoints: overall survival, objective response, clinical benefit response, patient-reported outcomes, pharmacokinetic effects and safety.

Safety and side effects

The most common grade 3 or 4 adverse events (palbociclib–letrozole vs placebo–letrozole): neutropenia 66.4% vs 1.4%, leucopenia 24.8% vs 0%, anaemia 5.4% vs 1.8% and fatigue 1.8% vs 0.5%.

Febrile neutropenia was reported in 1.8% of patients in the palbociclib–letrozole group and in none of the placebo–letrozole group.

Permanent discontinuation of any study drug because of adverse events: 43 patients (9.7%) in the palbociclib–letrozole group and 13 patients (5.9%) in the placebo–letrozole group.

Clinical significance and place in guidelines

Based on this abstract, adding palbociclib to letrozole as initial therapy for ER-positive, HER2-negative advanced disease significantly prolonged progression-free survival, confirming the phase 2 findings. This combination is associated with increased haematological toxicity (myelotoxicity). The status of drug approvals and the place of this regimen in current clinical guidelines should be checked separately.

Limitations

Overall survival results are not reported in the abstract. The primary endpoint was investigator-assessed. Haematological toxicity was higher in the palbociclib group. Dose details and other patient characteristics are not given in the abstract and the full text of the paper should be consulted. The study was funded by Pfizer.

Original article (DOI)PubMed ClinicalTrials.gov

This summary was prepared by the editorial team from the published paper; the original paper is the final reference. Read the original abstract on PubMed.