Immune checkpoint inhibitors: Primary care considerations

Primary healthcare practitioners are increasingly likely to care for people receiving, or recently treated with, an immune checkpoint inhibitor (ICI) as monotherapy or part of combined treatment for cancer. ICIs are monoclonal antibody treatments targeting checkpoints (receptor systems) in the immune system – these checkpoints regulate T-cells and their ability to recognise and target tumours.¹

In people with cancer, immune checkpoints can be co-opted by tumour cells to reduce T-cell activity and reduce immune responses to cancer. Use of an immune checkpoint inhibitor can increase T-cell activity and improve the immune response to tumours.^2,3 ICI action also results in increased T-cell activity against healthy cells and an increased risk of immune-related adverse effects, which can occur at any time, even months after the last dose of the ICI.^1,2

Two ICIs are now funded, as of 1 April 2023, for patients with locally advanced and metastatic non-small cell lung cancer (NSCLC) who meet the eligibility criteria.⁴ Pembrolizumab (Keytruda)⁵ and atezolizumab (Tecentriq)⁶ are two of a number of ICIs approved for use in New Zealand as treatments for NSCLC and a range of other cancers. Durvalumab (Imfinzi), another ICI, is funded for stage III, locally advanced, unresectable NSCLC as adjuvant therapy after definitive chemoradiation.⁷ Some other ICIs that may also benefit cancer patients are available only if funded privately.

The checkpoints targeted by pembrolizumab and atezolizumab are the programmed death-1 (PD-1) receptor and its ligand PD-L1, respectively.

• Pembrolizumab (Keytruda) is funded for the treatment of advanced NSCLC as first-line treatment, either as monotherapy or in combination with another agent.⁴
• Atezolizumab (Tecentriq) is funded for people with advanced NSCLC as second or later-line monotherapy.⁴

The full eligibility criteria for these ICIs are detailed in the 7 March funding decision.⁴

Equity considerations

Lung cancer is the leading cause of cancer-related death in Aotearoa. Most people with lung cancer are diagnosed with advanced disease, at the locally advanced or metastatic stage.

The incidence of NSCLC for Māori is threefold, and Pasifika twofold, compared with non-Māori non-Pacific peoples. Comparatively, Māori and Pacific peoples are also diagnosed at a younger age, with later-stage disease and experience worse outcomes from NSCLC.⁴

It is anticipated that the newly funded treatments for NSCLC will improve patient survival times and help achieve outcome equity, particularly for Māori and Pacific peoples. Additionally, better treatment may reduce the stigma associated with lung cancer, alleviating some of the less visible burden on patients.⁸

The eligibility criteria for pembrolizumab and atezolizumab have been constructed in a way that aims to remove barriers to treatment access (eg, a possible six-weekly intravenous infusion dosing regimen for pembrolizumab; three-weekly is the norm).

Pharmac estimates that, in the first year of funding, over 450 people with advanced NSCLC will begin treatment with pembrolizumab (increasing to over 700 per year after three years), and over 300 people with advanced NSCLC who have received prior chemotherapy will begin atezolizumab (decreasing to around 20 people per year after three years, as more people access first-line treatment).⁴ It is hoped that these measures, and an increased focus on early diagnosis, will contribute to achieving health equity and significant health benefits.

Pharmac has also created a temporary criterion for the first three months of funding to simplify the transition to publicly funded treatment for people currently on privately funded treatment or on compassionate access.

Increased early detection of lung cancer is vital to improving survival times. Primary care has an essential role in achieving this outcome by:

• considering lung cancer as part of the differential diagnosis in patients with symptoms that could be indicative of cancer
• identifying and assessing people with signs and symptoms of lung cancer and ensuring prompt referral and follow up for chest x-ray and secondary care assessment, as appropriate
• identifying and assessing people at high risk of lung cancer, and providing advice about when to seek medical attention if they become symptomatic
• ensuring care is provided in a non-judgemental way that focuses on the benefits of early detection.⁹

There are two main classifications of lung cancer – SCLC and non-small cell lung cancer (NSCLC), and each has its own staging system. NSCLC is the most common type (89 per cent of people in Aotearoa diagnosed with lung cancer between 2008 and 2012).¹⁰ SCLC tends to metastasise earlier, is more aggressive and harder to treat than NSCLC. SCLC is more common in Māori than non-Māori even after controlling for smoking status.⁹

(For a more detailed discussion, see “Early detection of lung cancer in primary care”. The article is based on expert guidance from the Te Aho o Te Kahu, Cancer Control Agency National Lung Cancer Working Group.)

People at high risk of lung cancer include those with a current or previous history of smoking, asbestos exposure, pre-existing lung disease, personal history of any cancer or family history of lung cancer.⁸

The key practice point for patient assessment is to have a high index of suspicion for lung cancer, as early detection increases the patient's chance of survival.¹¹

High suspicion of lung cancer should be raised by:

• any presentation of haemoptysis, in particular persistent or unexplained haemoptysis in patients aged >40 years
• persistent (more than three weeks) or unexplained:
  • cough
  • dyspnoea
  • chest or shoulder pain
  • hoarseness
  • chest signs on examination
  • digital clubbing
  • cervical or supraclavicular lymphadenopathy
  • weight loss
  • features suggestive of metastatic lung cancer, eg, to brain, bone or liver.¹¹

While chest x-ray is the first-line investigation for suspected lung cancer, a normal chest x‑ray does not exclude lung cancer. Specialist assessment is always required where any clinical concern remains, for example, where symptoms do not resolve and there is no positive alternative diagnosis.¹¹

Immune-related adverse events in patients receiving ICIs are common and affect a wide range of body systems, sometimes simultaneously.⁵ In clinical trials, most immune-mediated adverse reactions occurred during treatment; were reversible; and could be managed with interruptions of the ICI, administration of corticosteroids and/or supportive care in an oncology setting.⁵ However, severe and fatal cases have occurred in patients receiving pembrolizumab and atezolizumab.^5,6

For pembrolizumab and atezolizumab, immune-mediated adverse events include dysfunction or reactions affecting the:

• skin (>30 per cent of patients)
• gastrointestinal tract (5 to 15 per cent)
• thyroid (5 to 15 per cent)
• liver (5 to 15 per cent)
• nervous system (<5 per cent)
• lung (<5 per cent)
• pituitary (rare, mostly in males)
• body more widely; eg, DRESS – drug rash with eosinophilia and systemic symptoms (rare).²

The signs and symptoms of immune-related adverse effects are diverse and often non-specific, and the speed of onset and severity may differ from that seen with autoimmune diseases not caused by a drug reaction.²

Healthcare professionals need to become familiar with these reactions, which can range in severity from mild to serious and potentially fatal. As indicated by the list above, the most common immune-related adverse effects include skin rash, diarrhoea and colitis, thyroiditis and hepatitis. Rare adverse effects include primary adrenal insufficiency (Addison disease); colon perforation associated with enterocolitis; type 1 diabetes; renal, cardiac or ocular toxicity; and drug rash with eosinophilia and systemic symptoms (DRESS).¹

Comprehensive lists of adverse reactions to be aware of are detailed in the product data sheets for pembrolizumab (Keytruda)⁵ and atezolizumab (Tecentriq).⁶

Patients receiving pembrolizumab or atezolizumab for NSCLC will have any immune-related adverse events managed by their oncologist. However, to allow for this, the recognition of signs and symptoms of an adverse event are essential steps required of both the patient and primary healthcare teams, as is prompt communication with the patient’s oncologist.¹

This alertness to possible immune-related adverse events is equally important after ICI treatment has stopped. The safeguarding of patient wellbeing with regard to such adverse events must be a part of continued surveillance and “survivorship” as the patient transitions from active treatment to post-treatment care.¹²

(For a more detailed discussion, see “Lung cancer follow-up and surveillance: the role of primary care”. The article is based on expert guidance from the Te Aho o Te Kahu, Cancer Control Agency National Lung Cancer Working Group and includes a Checklist for Primary Care: caring for a patient post-treatment for lung cancer.)¹²

Advice for patients

Healthify (previously Health Navigator) provides useful online, printable information for patients receiving ICIs, and lists the common symptoms to be alert to as fatigue, nausea, diarrhoea, skin rash or pruritis, decreased appetite, joint pain, headache, or cough.¹³

While these symptoms are usually mild and resolve with time, patients are advised to report them to their oncology team rather than mange them alone.

If they have any of the signs and symptoms mentioned in the colour box below OR any new or worsening symptoms, patients are advised to urgently contact their healthcare team or Healthline on 0800 611 116.¹³

Incorporating the possibility of ICI adverse effects into your diagnostic framework

Many of the common symptoms of ICI adverse effects (eg, pruritus, headache, fatigue, arthralgia) can have numerous causes and therefore it is important, in all patient encounters, to ascertain the medical history, current treatments and – equally importantly – treatments stopped in the last six months or year.

Even with the relevant information, it may be difficult to tell whether the unwell patient is experiencing an adverse effect due to an ICI (or its earlier use), another cancer drug treatment, the cancer itself or an unrelated issue.

A precautionary approach to the signs and symptoms discussed here is required. The use of pembrolizumab or atezolizumab makes it more likely a patient’s immune system turns against healthy cells. Any sign of immune-mediated reactions should prompt urgent contact with the patient’s medical oncologist and treatment centre to allow an appropriate specialist review to be scheduled. Patients in primary care can be offered relief for minor symptoms, such as pruritus or headache, once the ICI prescriber alert or referral for review has been actioned.

Once a patient who is currently undergoing treatment with an ICI has been promptly returned to the oncology setting, appropriate management can begin. Severe adverse reactions require withholding the ICI until the severity grade is reduced; corticosteroid therapy or; in some more severe and life-threatening cases, permanent discontinuation of the ICI. Dose reduction is not a management option.^5,6

As with current patients, where the adverse reaction occurs in someone who has previously received an ICI, a prompt ICI-prescriber alert or referral for management in the oncology setting is essential.

Drug–drug interactions, safety profiles, blood tests

Both pembrolizumab and atezolizumab are cleared from the circulation through catabolism, and no metabolic drug-drug interactions are expected.^5,6

The safety profile for pembrolizumab is generally similar for patients with melanoma and NSCLC.⁵

Thyroid, liver (hepatic transaminase and bilirubin levels) and kidney function tests, and blood cell component testing are performed at the start of treatment, periodically during treatment and as indicated.^5,6

Vaccinations

There is clear guidance within the Ministry of Health Manatū Hauora Immunisation Handbook 2020 regarding vaccination of patients receiving ICI (immunostimulant) therapy.¹⁴

A person who is currently receiving any of the ICIs available in Aotearoa, or who has received these in the previous six months, can have any non-live vaccine – including influenza, mRNA-CV and rCV (COVID-19) – without consulting their specialist prior to vaccination. The administration of live vaccines (eg, MMR and varicella) is contraindicated during ICI treatment and for six months afterwards.¹⁴

COVID-19 vaccination is strongly encouraged for all people aged over 12 years, including those with cancer; follow national protocols for dosing advice.¹²

Pregnancy, breastfeeding and fertility

Pembrolizumab and atezolizumab are both Category D agents – they are not recommended during pregnancy unless the potential benefit for the mother outweighs the potential risk to the foetus. Pregnant women should be advised of the potential risk of foetal harm or loss of pregnancy. Women of childbearing potential should use effective contraception during treatment and for at least five months following the last dose of the ICI.^5,6

It is unknown whether either ICI is secreted in human breast milk. As the potential for harm to the nursing infant is unknown, a decision must be made to either discontinue breastfeeding or discontinue the ICI.^5,6

No fertility studies have been conducted. Preclinical safety studies in animals indicate atezolizumab may impair fertility in females of reproductive potential while receiving treatment.⁶ For pembrolizumab, no notable effects on male and female reproductive organs were observed in animal studies.⁵