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This content has been produced in line with the IBRANCE®▼ (palbociclib) Summary of Product Characteristics for Great Britain. This piece is intended for GB healthcare professionals only. 

This roundtable discussion has been commissioned and funded by Pfizer Ltd and developed in partnership with Guidelines in Practice. Please see bottom of page for full disclaimer.

Prescribing information and adverse event reporting information for IBRANCE® (palbociclib) for Great Britain can be accessed here

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Discussion group:

Sacha Howell (SH), Senior Lecturer and Honorary Consultant Medical Oncologist, The Christie NHS Foundation Trust

Rene Roux (RR), Consultant Medical Oncologist, Oxford University Hospital NHS Foundation Trust

Ian Purcell (IP), Advanced Pharmacist Practitioner, Nottingham University Hospital NHS Foundation Trust

Catherine Bailey (CB), MacMillan Breast Cancer Nurse Consultant, Royal Berkshire NHS Foundation Trust

Abstract

This supplement reports on a round table discussion which explored best practice in treating patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2–) advanced breast cancer (ABC). Expert panel members described their rationale behind the use of cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors in combination with endocrine therapy (ET) over chemotherapy, where appropriate, including for those patients with complex disease, and the factors involved in making those prescribing decisions. They discussed how they challenge themselves to use CDK4/6 inhibitors in more complex cases, providing examples of patients they have treated.

The panel also discussed the ways in which CDK4/6 inhibitor clinics are run in their trusts and recent changes that have been implemented to aid the smooth-running of these clinics in day-to-day practice.

Introduction

The treatment landscape for HR+/HER2– ABC is continually changing, notably since 2016 through the introduction of CDK4/6 inhibitors in combination with ET. 

Current European School of Oncology (ESO)-European Society of Medical Oncology (ESMO) and the National Institute for Health and Care Excellence (NICE) guidelines for ABC recommend ET as the preferred option for HR+ disease, even in the presence of visceral disease, unless there is visceral crisis.1,2 Chemotherapy is currently recommended as the first-line treatment for those patients with HR+ ABC whose disease is imminently life-threatening or requires early relief of symptoms because of significant visceral organ involvement, providing they understand and are prepared to accept the increased toxicity.2  

For patients with HR+/HER2– ABC, ESO-ESMO recommends a CDK4/6 inhibitor combined with ET as the standard of care since it achieves a substantial progression-free survival benefit, significantly increases overall survival, and either maintains or improves quality of life (QoL).1  

Despite this, chemotherapy continues to be prescribed as a first-line treatment. One study, prior to the introduction of CDK4/6 inhibitors, found that a quarter of patients with HR+/HER2– ABC were given chemotherapy as first-line treatment despite lower efficacy (median progression-free survival: 5.3 vs 13.3 months; median overall survival: 16.1 vs 36.9 months) and higher rates of toxicity compared with ET.3 In a more recent study from Germany, the introduction of CDK4/6 inhibitors resulted in a reduction in first line chemotherapy from 42.2% to 27.2% over 4 years. Concomitantly the use of single agency ET fell from 53.0% to 9.5% and the use of CDK4/6 inhibitors + ET increased to 62.7%.4 Whilst changes in clinical practice have been made, the uptake of CDK4/6 inhibitors in routine clinical practice has been found to vary significantly across the UK.5

Expert panel recommendations for treating patients with CDK4/6 inhibitors

  • Clinicians should consider a CDK4/6 inhibitor with ET as the standard of care for patients with HR+/HER2- even in patients with visceral disease, unless there is visceral crisis
  • Chemotherapy remains the standard of care in visceral crisis
  • There are nuances in the definition of ‘visceral crisis’ and group consensus is treatment decisions should be made at the discretion of the individual clinician and/or MDT
  • Group consensus is that patients in ‘imminent visceral crisis’ can still be treated with CDK4/6 inhibitors, where appropriate
  • Sharing of experience in using CDK4/6 inhibitors amongst HCPs is encouraged to increase confidence in prescribing, especially with less clear-cut cases
  • Quality of life should be considered a key factor in determining treatment choice  
  • Pharmacist- and nurse-led clinics can help reducing capacity strains in certain trusts 
  • Remote consultations and follow up may be beneficial for patients and clinicians alike but should be tailored to individual patient needs 
  • Virtual clinics may provide a solution to further reduce capacity strains.

CDK=cyclin-dependent kinase; ET=endocrine therapy; HCP=healthcare professional;
HER2–=human epidermal growth factor receptor 2 negative; HR+=hormone receptor-positive; MDT=multidisciplinary team.

CDK4/6 inhibitors or chemotherapy? 

The group agreed their default position is to use a CDK4/6 inhibitor with ET first line for patients with HR+/HER2- ABC unless there is visceral crisis, supported by the recommendations in ESO-ESMO and NICE guidelines.1,6  

RR started by stating: ‘I think in the first-line setting you really have to qualify why you are not going to use a CDK4/6 inhibitor.

In his role as advanced pharmacist practitioner, IP described treatment decisions made in weekly ABC multidisciplinary team (MDT) meetings: ‘If someone is HR+ it is almost taken as a given that treatment will be with a CDK4/6 inhibitor unless there is a clinical risk. I’ve seen different ways of deciding how big that risk is without necessarily defining them as visceral crisis. Any adjuvant treatments and any progression or development of disease while on adjuvant treatment might guide what we use for that patient, but then it tends to be going for a second-line CDK4/6 inhibitor with fulvestrant.’

Panel members discussed how the main factor contributing to a treatment decision between a CDK4/6 inhibitor with ET versus chemotherapy was whether a patient was in visceral crisis, however they explained that there are nuances in how ‘visceral crisis’ can be defined, which are not described in the guidance. 

The panel agreed that whilst there may be different factors that all contribute to whether a patient may be in visceral crisis, such as increased alanine transaminase (ALTs) or aspartate transaminase (ASTs), increased bilirubin levels, or significant visceral burden of metastasis, there is no one factor that defines it and they must look holistically at the patient whilst also taking patient preference into account to determine the right treatment. RR explained how bilirubin levels may be used to guide her treatment choice; ‘‘in terms of liver function tests (LFTs), I’m not too fussed about the ALT or ALP (alkaline phosphatase), but a high bilirubin would push me more into the arena of this is getting into visceral crisis and we need to claw this back very quickly’.  

SH explained how ‘the recent emergence of the phrase “imminent visceral crisis” within clinical practice really goes some way to show that this isn’t a cast iron definition and there is some room for manoeuvre’. As clinicians see more patients with imminent visceral crisis, where the criteria for visceral crisis are not yet met but may be foreseen to happen, they should continue to challenge themselves to expand the use of CDK4/6 inhibitors into these patient groups, if appropriate.  

Because of this, the panel agree that whilst the guidance is there to help, the decision should be made at the discretion of the individual clinician or MDT panel but agreed that as experience and confidence increases, clinicians could challenge these factors and push the boundaries on where CDK4/6 inhibitors can be used.

A shift in clinical practice 

The experts described a gradual shift in practice in their trusts from using chemotherapy to CDK4/6 inhibitors in the years since CDK4/6 inhibitors first became available, now resulting in an expansion of their use of CDK4/6 inhibitors into multiple patient groups. As clinicians have gained more experience with using CDK4/6 inhibitors in different types of patients, they are more familiar with their effectiveness and how well patients tolerate treatment. SH explained that the first patients treated with CDK4/6 inhibitors were in clinical trials: ‘in those trials, patients with transaminases over 5x the upper limit of normal or a bilirubin of 1.5x the upper limit of normal wouldn’t have been eligible, so we had no experience of treating such patients with CDK4/6 inhibitors until they became approved. Since then, we have started to expand their use into the groups who wouldn’t have been previously eligible for inclusion in clinical trials’. As more data becomes available and clinician experience increases, this gradual shift is expected to be seen to expand across all trusts in the UK.

The panel suggests that the reasons why some trusts may still see high chemotherapy first-line use in cases where CDK4/6 inhibitors would be more suitable may be due to less experience within the trust, resulting in a lack of confidence. As clinicians across the UK continue to expand their experience of prescribing CDK 4/6 inhibitors, confidence in how to manage appropriate patients on CDK4/6 inhibitors should follow. This should see increased early use of CDK4/6 inhibitors as standard of care in the UK with positive patient outcomes. 

Effect on quality of life

CDK4/6 inhibitors have several benefits for patients, including enabling them to have more treatment at home and requiring fewer hospital visits. CB outlined how the medicine: ‘allows people to get on with their life more easily than chemotherapy does, which is a lot more regimented about what they can and can’t do, and where they can and can’t go, and therefore is a good choice of treatment for many people’.

The experts rated the impact of treatment on patients’ QoL as very important. They described how effectively controlling a patient’s cancer and reducing their symptoms is the best way to improve their quality of life. As CB explained: ‘women with secondary breast cancer say they feel better if their cancer is controlled. If they feel their cancer is progressing their QoL goes down; if they feel their cancer is controlled their QoL is better. And psychologically, if they feel their treatment is working, they can better manage their low-level symptoms, and readjust how they feel about things’.

It is important to explain to patients that one of the aims of treatment is to improve their QoL, particularly if they have had issues with tolerability or a poorer QoL on any prior chemotherapy treatment. RR described how: ‘it’s quite nice to be able to say, “actually, what we have to offer you now is very different, it’s an alternative to chemotherapy and it’s better tolerated – it should improve your QoL”’. 

Managing any side effects of CDK4/6 inhibitors as well as those experienced with ET will improve QoL and encourage patients’ compliance with treatment. Patients sometimes expect the side effects from CDK4/6 inhibitors to be as troublesome as those experienced on chemotherapy and are often relieved to find they are more manageable.

CDK4/6 inhibitor clinics 

As the ABC landscape has evolved with the introduction of CDK4/6 inhibitors, so has the management of ABC patients throughout trusts.  It has been necessary to make changes to services to ensure that the best possible care can continue to be delivered to patients and support in reducing capacity strains. 

The experts described the different ways in which CDK4/6 clinics were run in their trusts. Some trusts utilise pharmacist or nurse led clinics that run in parallel with consultant clinics. IP explained how pharmacist- and nurse-led clinics have reduced pressures on capacity in consultant clinics, allowing consultants more time to focus on complex cases and seeing new patients. ‘An added benefit’ IP discussed ‘is that pharmacy and nursing practitioners do not rotate to other areas, allowing for continuity of care for patients who see the same person in clinic each appointment, and specialist support for the clinician team.’

Remote consultations and home delivery services for medication including CDK4/6 inhibitors is also available, with the COVID-19 pandemic hastening the implementation of these in many cases.  If patients on treatment are stable, certain trusts are now able to follow up with patients remotely, and can dispense two or 3 months’ medication at a time. Patients can also have blood tests at their local GP practice. 

Remote consultations and home delivery of medicines benefit patients in terms of time by reducing their need to travel to hospital so frequently. Avoiding hospital also reduces their risk of infections, particularly during the COVID-19 pandemic. However, remote consultations do not suit everyone for differing reasons. Some patients may be reassured by seeing a healthcare professional face to face, and some may require regular clinical examination to assess symptoms and disease status, so patients should be given a choice and clinicians should try and proactively identify which model best suits each patient. 

Patients should always be counselled to contact their breast cancer clinic if they feel unwell and be reassured that they are able to attend even if having remote consultations. Thorough patient education is therefore key to effective remote consultations, so that patients are aware of the signs and symptoms that mean they should contact their clinic urgently rather than waiting for their next face-to-face appointment.

IP described plans to introduce virtual clinics for stable patients between scans that will use patient-reported outcome measures (PROMs), which have proven successful in other areas of care. Patients are given a questionnaire, and if their answers indicate there are no issues in terms of side effects and change in grading, then their CDK4/6 inhibitors can be prescribed and dispensed without the need for even a telephone consultation. If, however, they answer a question that indicates a potential problem, it will automatically send a message to the oncology triage line to prompt a discussion with the patient to ascertain if further assessment or treatment is required. Monthly telephone consultations will still be needed for those patients who find them reassuring but this system will enable many patients to feel less tied to the hospital and get on with their life, which may improve their QoL.

A benefit of using PROMs is that they provide consistency and trends over time, as information about toxicity and QoL are provided by the same patient rather than by different healthcare professionals, so providing rich data that will help with treatment decisions.

Case studies

The panel agreed that sharing of complex cases amongst peers is the best way to increase confidence in prescribing. Some of the panel members have shared cases in which they selected a CDK4/6 inhibitor with ET as opposed to chemotherapy for patients with HR+/HER2– ABC with more complex disease. 

Case study 1

A 27-year-old woman had de novo presentation of HR+/HER2– ABC, with a proven biopsy from the breast. She had a bilirubin of 29µmol/l, just under 1.5x the upper limit of normal defined in the ESO-ESMO guidance as an example of visceral crisis.1 She had very high AST and ALP, and a cancer antigen (CA) 15-3 of 4500. Her liver was very large and she was highly symptomatic, having experienced symptoms for 3 or 4 months. Extensive bilobar enlargement resulted in bilateral shoulder pain. 

As she had not had any exposure to ET, it was decided to treat her with a CDK4/6 inhibitor, because her response rate should be higher than with chemotherapy. She responded rapidly with improvement in her symptoms and liver function tests within 2 weeks, although her CA 15-3 increased to 6000 and only started reducing after 2 months. CDK4/6 inhibitor + ET were continued and her disease has responded on CT scans at 3 and 6 months. Her quality of life has improved dramatically with resolution of all cancer related symptoms and she is now (as of August 2021) back at work and enjoying life.

Case study 2 

A woman in her early 50s presented at the beginning of 2019 to her GP with dyspepsia and reflux. Bloods showed that she had deranged LFTs, with a bilirubin of 48µmol/litre. She had a history of breast cancer in 2010 and the GP referred her back to oncology with a request for staging scans. This showed extensive liver disease and a degree of retroperitoneal lymphadenopathy. The patient refused chemotherapy because of a previous bad experience with side effects, so she was trialled with a CDK4/6 inhibitor after explaining to her that this was a different type of treatment.

Within a couple of weeks her symptoms had improved. Before she had any radiological response, her LFTs started to improve, and her CA 15-3 came down quite well. Her CA 15-3 was 872 in July 2019 at relapse, 279 in Oct 2019 after 3 months of treatment and normalised to 15 by July 2020. The first scan showed stable disease but her last three scans have all shown continued complete radiological response at both sites and her QoL has improved. 

Case study 3

A 62-year-old woman presented in January 2019 with widespread bone metastases and small-volume liver metastases. She had numbness all around her face from the metastases at the base of her skull and a destructive lesion in the top of her skull. She could hardly walk. Her ALT was raised but other LFTs were normal and she had a low platelet level. She was given a CDK4/6 inhibitor and an AI because the bone metastases were so unstable and widespread. Her scan 18 months after diagnosis showed her liver metastases were no longer visible and her bone disease was stable. Her platelet level returned to normal over the initial 6-month period. Her QoL has greatly improved and she is much more mobile able to walk her dog 2 or 3 miles a day. Her disease currently remains stable.

IBRANCE® safety profile

  • The overall safety profile of IBRANCE is based on pooled data from 872 patients who received IBRANCE in combination with ET (n=527 in combination with letrozole and n=345 in combination with fulvestrant) in randomised clinical studies in HR+ HER2− ABC7
  • The most frequent (≥20%) adverse reactions of any grade reported in patients receiving IBRANCE in randomised clinical studies were neutropenia, infections, leucopenia, fatigue, nausea, stomatitis, anaemia, diarrhoea, alopecia and thrombocytopenia7
  • The most frequent (≥2%) Grade ≥3 adverse reactions with IBRANCE were neutropenia, leucopenia, infections, anaemia, AST increased, fatigue and ALT increased7
  • ILD/pneumonitis was reported in 12 patients (1.4%)7

Please refer to the IBRANCE Summary of Product Characteristics for full safety profile information.7

Conflicts of interest

The group members have received an honorarium to participate to this roundtable discussion. They have also received consultancy fees from other pharmaceutical companies, which may include Pfizer Ltd, for activities other than participating in this roundtable discussion. 

References

Adverse events should be reported.  Reporting forms and information can be found at www.mhra.gov.uk/yellowcardor search for MHRA Yellow Card in the Google Play or Apple App Store. Adverse events should also be reported to Pfizer Medical Information on 01304 616161.

This roundtable discussion has been commissioned and funded by Pfizer Ltd and developed in partnership with Guidelines in Practice. Pfizer Ltd suggested the topic and group members, and carried out full medical approval on all materials to ensure compliance with regulations. The group members have been paid honoraria. The views and opinions of the group members are not necessarily those of Guidelines in Practice, its publisher, advisers, or advertisers. No part of this publication may be reproduced in any form without the permission of the publisher. 

This content has been produced in line with the IBRANCE® (palbociclib) Summary of Product Characteristics for Great Britain. This piece is intended for GB healthcare professionals only.

PP-IBR-GBR-3703
Date of preparation: October 2021