Role of palbociclib in advanced breast cancer: ESO-ESMO 2020 guidelines and clinical insights
Latest 2020 guidelines of the European School of Oncology (ESO) and European Society for Medical Oncology (ESMO) recommend the use of cyclin-dependent kinase (CDK) 4/6 inhibitors, such as palbociclib (Ibrance®, Pfizer), combined with endocrine therapy (ET) as the standard of care (SoC) for first- and second-line treatment of advanced hormone receptor (HR)-positive and HER2-negative breast cancer (BC) in pre-, peri- and postmenopausal patients based on studies showing progression-free (PFS) improvement and maintenance of health-related quality of life (HRQoL). Palbociclib is well tolerated and its adverse events (AEs) can be easily managed. In an interview with MIMS Oncology, Dr Tracy Lau, specialist in clinical oncology in Hong Kong, discussed the role of palbociclib as a treatment option for advanced BC in premenopausal patients.
ESO-ESMO 2020 guidelines on management of HR-positive, HER2-negative advanced BC
“The latest 5th ESO-ESMO guidelines on advanced breast cancer [ABC5] regard palbociclib in combination with an aromatase inhibitor [AI; eg, letrozole] or oestrogen receptor antagonist [eg, fulvestrant] as the SoC for first- and second-line treatment of HR-positive HER2-negative, de novo or recurrent ABC in pre-, peri- and postmenopausal patients,” said Lau. “While it remains unclear whether CDK 4/6 inhibitors should preferably be used in the first- or second-line setting, the majority of ABC5 panellists preferred using it in the first line for the majority of their patients.” [Ann Oncol 2020, doi: 10.1016/j.annonc.2020.09.010]
For young women with HR-positive ABC, the guidelines recommend adequate ovarian function ablation (OFA) or ovarian function suppression (eg, with a luteinizing hormone-releasing hormone [LHRH] agonist), followed by the same treatment given to postmenopausal patients.
PALOMA-3: Palbociclib improves PFS
In the randomized PALOMA-3 trial, pre-, peri- and postmenopausal patients aged ≥18 years (n=521; European Cooperative Oncology Group Performance Status [ECOG PS], 0–1) with HR-positive HER2-negative metastatic BC who had disease progression on prior ET were randomized (2:1) to receive palbociclib (125 mg/day, orally for 3 weeks followed by 1 week off over 28-day cycles) plus fulvestrant (500 mg intramuscular injection on days 1 and 15 of cycle 1, then on day 1 of subsequent 28-day cycles) (n=347), or placebo plus fulvestrant (n=174) as second-line treatment. Goserelin was also given to premenopausal and perimenopausal women. [N Engl J Med 2015;373:209-219]
Results of the final analysis, after a median of follow-up of 8.9 months, showed a significant improvement in progression-free survival (PFS) with palbociclib plus fulvestrant vs placebo plus fulvestrant (median, 9.5 months vs 4.6 months; hazard ratio, 0.46; 95 percent confidence interval [Cl], 0.36 to 0.59; p<0.0001). [Lancet Oncol 2016;17:425-439]
The median overall survival (OS) was 34.9 months in the palbociclib plus fulvestrant group vs 28.0 months in the placebo plus fulvestrant group (hazard ratio, 0.81; 95 percent CI, 0.64 to 1.03; p=0.09). [N Engl J Med 2018;379:1926-1936]
Benefit in premenopausal and Asian women
Subgroup analysis revealed consistent PFS benefit of palbociclib plus fulvestrant vs placebo plus fulvestrant (9.5 months vs 5.6 months; hazard ratio, 0.50; 95 percent CI, 0.29 to 0.87; p=0.013) among premenopausal women (n=108; mean age, 45 years), who accounted for 20.7 percent of the overall trial population. (Figure) [Oncologist 2017;22:1028-1038]
A similar PFS benefit with palbociclib plus fulvestrant was observed in postmenopausal women (9.9 months vs 3.9 months; hazard ratio, 0.45; 95 percent CI, 0.34 to 0.59; p<0.0001). [Oncologist 2017;22:1028-1038]
“PFS improvement with palbociclib vs placebo was comparable between Asians and non-Asians,” said Lau. Median PFS in Asians was not reached (NR) with palbociclib vs 5.8 months with placebo (hazard ratio, 0.485; 95 percent CI, 0.270 to 0.869; p=0.0065), and was 9.5 months vs 3.8 months (hazard ratio, 0.451; 95 percent CI, 0.34 to 0.59; p<0.001) in non-Asians. [J Glob Oncol 2017;3:289-303]
“Furthermore, global quality of life [QoL] was maintained with no significant deterioration in patient-reported outcomes [PROs] from baseline among Asian patients in the palbociclib arm,” she added.
In terms of safety, neutropenia was the most frequently reported AE of all grades (81 percent in the palbociclib group vs 4 percent in the placebo group) in the PALOMA-3 trial, with grade 3/4 neutropenia occurring predominantly in the first month. [Lancet Oncol 2016;17:425-439; Oncologist 2016;21:1165-1175] In the palbociclib arm, 28 percent of patients had one dose reduction and 6 percent had two dose reductions, with the median duration of dose interruption or delay being 6.0 days and 2.5 days, respectively. Subsequent grade 4 neutropenia occurred in only 4.8 percent of patients who had dose reduction owing to neutropenia. [Oncologist 2016;21:1165-1175]
“Remarkably, neither dose modification of ≥1 dose for neutropenia [p=0.45] nor dose interruption or cycle delay [p=0.31] had an adverse impact on the efficacy of palbociclib,” Lau pointed out.
Compared with other CDK 4/6 inhibitors, palbociclib appears to have a better gastrointestinal tolerability profile. In a phase III trial, the rate of diarrhoea with abemaciclib plus fulvestrant vs placebo plus fulvestrant was 86.4 percent vs 24.7 percent, while the rate of nausea was 45.1 percent vs 22.9 percent. In PALOMA-3, rates of diarrhoea and nausea in the palbociclib vs placebo group were 21.4 percent vs 18.6 percent and 32.5 percent vs 27.3 percent, respectively,” said Lau. [J Clin Oncol 2017;35:2875-2884; Oncologist 2016;21:1165-1175] “In the case of ribociclib, prolonged QT interval on electrocardiogram [11 percent for ribociclib vs 4 percent for placebo] and increase in liver enzymes [24 percent vs 16 percent] warrant liver function and ECG monitoring.” [Lancet Oncol 2018;19:904-915]
Hong Kong experience with palbociclib
“Palbociclib has demonstrated good clinical response and is well tolerated in our patients. Rates of all-cause grade 3/4 AEs reported in Hong Kong are comparable to those observed among Asian patients within the subgroup analysis of the PALOMA-3 trial, [with neutropenia, leukopenia and febrile neutropenia occurring in 92 percent, 29 percent and 4.1 percent of Asian patients in PALMOA-3, respectively],” said Lau. [J Clin Oncol 2017;35:2875-2884]
“In our experience, neutropenia usually emerges 15 days after the first dose of palbociclib. The timing of adequate monitoring is thus important,” she suggested.
Additional monitoring of complete blood count (CBC) may be necessary based on individual circumstances. It is advised to monitor patients’ CBC prior starting palbociclib, at the beginning of each cycle, on day 14 of the first two cycles, and as clinically indicated. Results of CBC monitoring may necessitate subsequent dose modification. [Ibrance prescribing information]
“CDK 4/6 inhibitors, such as palbociclib, are unanimously recommended as the SoC for treatment of advanced BC by various international guidelines. It is important to be aware of the unique AE profiles of different CDK 4/6 inhibitors, with regular monitoring and AE management put in place,” Lau concluded.