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Increasing role of palbociclib in management of advanced breast cancer

Dr. Jessica Lai
Specialist in Clinical Oncology in Hong Kong
04 Jun 2020

Current international guidelines on management of advanced hormone receptor (HR)-positive and HER2-negative breast cancer (BC) recommend the use of cyclin-dependent kinase (CDK) 4/6 inhibitors, such as palbociclib (Ibrance®, Pfizer), in the first- and second-line settings in both pre-, peri- and postmenopausal patients based on the progression-free survival (PFS) and health-related quality of life (HRQoL) improvements. In Hong Kong, the financial coverage for palbociclib under the Community Care Fund (CCF) Medical Assistant Programme was recently extended to patients with non-visceral metastases, allowing a greater number of patients to benefit from new treatment option. In an interview with MIMS Oncology, Dr Jessica Lai, Specialist in Clinical Oncology in Hong Kong, discussed the increasing role of palbociclib as a first- and second-line treatment option for advanced BC.

Current recommendations for managing HR-positive, HER2-negative advanced BC

Current international guidelines recommend the use of palbociclib in combination with an aromatase inhibitor (AI; eg, letrozole) or the oestrogen receptor antagonist fulvestrant as first-line therapy for pre-, peri- and postmenopausal women with HR-positive, HER2-negative advanced BC. [NCCN Clinical Practice Guidelines in Oncology, Breast Cancer, version 2.2020; Ann Oncol 2018;29:1634-1657; National Institute for Health and Care Excellence (NICE) technology appraisal guidance TA619: www.nice.org.uk/guidance/ta619/chapter/1-Recommendations; NICE technology appraisal guidance TA495: www.nice.org.uk/guidance/ta495/resources; J Clin Oncol 2016;34:3069-3103]

In pre- or perimenopausal patients, palbociclib can be used, in combination with an AI, when ovarian ablation or suppression with a luteinizing hormone-releasing hormone agonist is given. [Ibrance prescribing information]

Role of palbociclib in HR-positive, HER2-negative advanced BC

“The CDK 4/6 inhibitors are now the gold-standard treatment for HR-positive, HER2-negative advanced BC,” said Lai. Palbociclib is a highly selective, reversible inhibitor of CDK 4/6, and elicits cell cycle inhibition downstream of multiple oncogenic and tumour suppressive pathways. [Ibrance prescribing information; Trends Cancer 2017;3:39-55]

PALOMA-2 trial

In the double-blind, phase III, PALOMA-2 study, 666 postmenopausal women (Eastern Cooperative Oncology Group Performance Status [ECOG PS] 0–2) with HR-positive, HER2-negative advanced BC who were not previously treated for advanced disease were randomized (2:1) to receive first-line treatment with either palbociclib (125 mg/day, orally for 3 weeks followed by 1 week off over 28-day cycles) plus letrozole (2.5 mg/day, orally) (n=444; median age, 62 years), or matching placebo plus letrozole (n=222; median, 61 years). At baseline, 51.4 percent and 22.7 percent of all patients had non-visceral metastases and bone-only disease, respectively. [N Engl J Med 2016;375:1925-1936]

At a median follow-up of 23 months, a significant improvement in investigator-assessed PFS was seen in the palbociclib vs placebo group (median, 24.8 months vs 14.5 months; hazard ratio, 0.58; 95 percent confidence interval [CI], 0.46 to 0.72; p<0.001).

A consistent PFS benefit with palbociclib-letrozole was demonstrated across all subgroups, with a remarkable benefit seen among those with bone-only disease at baseline (hazard ratio, 0.36; 95 percent CI, 0.22 to 0.59). [N Engl J Med 2016;375:1925-1936] Asian patients were found to obtain a comparable PFS benefit from palbociclib-letrozole (25.7 months vs 13.9 months; hazard ratio, 0.48; 95 percent CI, 0.27 to 0.87) compared with the overall population. [J Glob Oncol 2019;5:1-19]

The confirmed objective response rate was 42.1 percent for palbociclib-letrozole vs 34.7 percent for placebo-letrozole (odds ratio [OR], 1.40; 95 percent CI, 0.98 to 2.01; p=0.06) , while the clinical benefit response (defined as a confirmed complete response, partial response, or stable disease for ≥24 weeks) was 84.9 percent vs 70.3 percent (OR, 2.39; 95 percent Cl, 1.58 to 3.59; p<0.001). [N Engl J Med 2016;375:1925-1936]

Extended follow-up analysis at approximately 38 months revealed a continuous improvement in investigator-assessed PFS (median, 27.6 months vs 14.5 months; hazard ratio, 0.563; 95 percent CI, 0.461 to 0.687; p<0.0001) with palbociclib-letrozole vs placebo-letrozole. A substantial benefit in PFS with palbociclib-letrozole was observed across all subgroups, particularly in patients with bone-only disease (median, 36.2 months vs 11.2 months; hazard ratio, 0.406; 95 percent CI, 0.262 to 0.630; p<0.0001) and those who did not receive prior endocrine therapy (ET) (median, 36.2 months vs 27.6 months; hazard ratio, 0.591; 95 percent CI, 0.378 to 0.923; p<0.01). (Figure 1) [Breast Cancer Res Treat 2019;174:719-729]

HK-PFI-690mo 01

There was no significant difference in patient-reported (PR) HRQoL between the palbociclib-letrozole and placebo-letrozole arms (p=0.629), as assessed by overall change from baseline in Functional Assessment of Cancer Therapy-Breast (FACT-B) total scores.

PALOMA-3 trial

In the PALOMA-3 trial, women aged 18 years (n=521; ECOG PS, 0–1) with HR-positive, HER2-negative metastatic BC who had disease progression on previous ET were randomized (2:1) to receive palbociclib 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. [N Engl J Med 2015;373:209-219]

Results of the final analysis, after a median follow-up of 8.9 months, showed a significant improvement in PFS with palbociclib plus fulvestrant vs placebo plus fulvestrant (median, 9.5 months vs 4.6 months; hazard ratio, 0.46; 95 percent CI, 0.36 to 0.59; p<0.0001). [Lancet Oncol 2016;17:425-439]

The PFS benefit with palbociclib-fulvestrant was observed in all patients regardless of their menopausal status (pinteraction=0.89). Among pre- and perimenopausal patients (which accounted for 20.7 percent of all enrolled patients), the median PFS was 9.5 months vs 5.6 months (hazard ratio, 0.50; 95 percent CI, 0.29 to 0.87) in the palbociclib-fulvestrant group vs placebo-fulvestrant group. A similar improvement in PFS was seen among postmenopausal patients treated with palbociclib-fulvestrant vs placebo-fulvestrant (median, 9.9 months vs 3.9 months; hazard ratio, 0.45; 95 percent CI, 0.34 to 0.59). (Figure 2)

HK-PFI-690mo 2

Assessment of PR outcomes showed that palbociclib-fulvestrant was associated with a significant improvement in estimated overall global QoL scores (66.1 vs 63.0; p=0.0313) and a significant reduction from baseline in pain (-3.3 vs 2.0; p=0.0011) compared with placebo-fulvestrant. [Ann Oncol 2016;27:1047-1054]

Among Asians, neutropenia (89.2 percent for palbociclib-fulvestrant vs 3.3 percent for placebo-fulvestrant), leucopenia (32.3 percent vs 0 percent) and anaemia (6.2 percent vs 6.7 percent) were the most common grade 3/4 adverse events (AEs). Palbociclib dose reductions and interruptions/delays due to AEs were required in 56.9 percent of patients. Treatment discontinuation due to AEs occurred in 10.8 percent vs 6.7 percent of palbociclib-letrozole vs placebo-fulvestrant recipients. [J Glob Oncol 2019;5:1-19]

“Nevertheless, a previous study showed that dose modifications for grade 3/4 neutropenia had no adverse impact on PFS, suggesting that patients should be on palbociclib for as long as possible,” said Lai. [Oncologist 2016;21:1165-1175]

HK experience with palbociclib

“Palbociclib has demonstrated good clinical response and QoL outcomes. It is used as the initial treatment in half of my patients; among them, 30 percent have non-visceral metastasis. Half of all the patients treated with palbociclib in the first- and second-line settings have had the dose reduced, whilst only 6 percent had treatment discontinued due to drug toxicity,” said Lai.

“One of my patients, who was found to have solitary bone metastasis and abdominal lymph node metastases on postoperative PET scan, has been on palbociclib-letrozole since May 2017. Given the AE of neutropenia, her palbociclib dose was reduced in a stepwise fashion, eventually down to 75 mg on day 1–21 Q6W. She has continued to derive clinical benefit from palbociclib, without disease progression,” she continued. “Therefore, with close monitoring and dose interruption or reduction as required, AEs can be reduced whilst maintaining treatment efficacy.”

Extension of CCF coverage

“Financial coverage for palbociclib under the CCF Medical Assistant Programme in Hong Kong has recently been extended to patients with locally advanced BC with non-visceral metastases since January 2020. This extension of coverage has led to a significant change in our local practice. I am delighted to see that many more patients in Hong Kong will be able to benefit from this extension,” said Lai. [Items Supported by the CCF Medical Assistance Programmes: https://www.ha.org.hk/visitor/ha_visitor_index.asp?content_id=254464]

“The decision on extension of CCF coverage was made based on the positive trial results and international guidelines, whereby the same benefits of palbociclib were demonstrated in all prespecified subgroups of patients, including those with non-visceral metastases and those who were pre- or perimenopausal in the PALOMA-2 and PALOMA-3 trials, respectively,” she noted.

Take-home message

“Current international guidelines advocate the use of palbociclib upfront in pre-, peri- and postmenopausal women with HR-positive, HER2-negative advanced BC. With close monitoring, and dose modification when required, patients are able stay on treatment, without further disease progression, whilst maintaining QoL,” Lai concluded.

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Most Read Articles
14 Feb 2020
The phase III CASTOR and POLLUX studies previously demonstrated benefit of daratumumab plus bortezomib and dexamethasone (DVd) or lenalidomide and dexamethasone (DRd) vs standard-of-care (SoC) Vd or Rd regimen in relapsed or refractory multiple myeloma (R/R MM). The latest efficacy and safety results after 4 years of follow-up from CASTOR and POLLUX were presented at the American Society of Hematology (ASH) 61st Meeting & Exposition 2019 held in Orlando, Florida, US.  
Prof. Mark Shackleton, 01 Apr 2020
In recent years, the focus on immuno-oncology has generated a wealth of compelling evidence supporting the use of immune checkpoint inhibitors – in particular those targeting the programmed death-ligand 1 (PD-L1) or PD-1 pathway. At the 8th Oncology Summit organized by the Hong Kong Society of Clinical Oncology, Professor Mark Shackleton of Alfred Health and Monash University, Australia, discussed recent advances in immunotherapy for the management of metastatic Merkel cell carcinoma (MCC) with a focus on the role of the PD-L1 inhibitor avelumab.  
Dr. Jason Butler, 01 Apr 2020
Proteasome inhibitors have become a cornerstone of therapy for multiple myeloma (MM). At the Hong Kong Society of Myeloma Annual Scientific Meeting 2019, Dr Jason Butler of the Icon Cancer Care & Royal Brisbane and Women’s Hospital, Brisbane, Australia, reviewed current evidence for the use of proteasome inhibitors in the management of relapsed/refractory MM (R/R MM), with a focus on the efficacy and safety profile of carfilzomib.
Dr. Tai-Chung Lam, 14 Feb 2020
While the armamentarium of therapies for metastatic non-small-cell lung cancer (NSCLC) has evolved to include various targeted therapies and immunotherapeutic agents, combinations with optimal efficacy and tolerability remain to be elucidated. At the 8th Joint Scientific Meeting of the Royal College of Radiologists (RCR) and Hong Kong College of Radiologists (HKCR) and 27th Annual Scientific Meeting of HKCR, Professor Tai-Chung Lam of the Department of Clinical Oncology, the University of Hong Kong, discussed the use of immunotherapy-based combinations for the management of EGFR-mutated NSCLC, with an emphasis on the role of the anti–PD-L1 antibody, atezolizumab.