Immunotherapy in Palliative Care

Dr Anna Olsson-Brown

MRC Clinical FellowMedical Oncology Registrar

Deputy Chair of the IO Committee, CCC

Oncological Immune Checkpoint Inhibitors

Hanahan D, Weinberg RA. Hallmarks of Cancer: The next generation. Cell. 2011. 144(5):646-674

Unifying hallmarks of cancer revealed several targets for further drug development

Hallmarks of Cancer

A Wide Field

Immunotherapy

Monoclonal Antibodies

Checkpoint Inhibitors

CTLA4

ipilimumab

PD1

nivolumab

pembrolizumab

Oncoolytic virus therapy

T-Cell Therapy Cancer VaccinesNon-specific

Immunotherapy

Interferons

interleukins

Olsson-Brown, Harker. 2018. Guidelines in Practice

The impact of IO in melanoma

One year overall survival has increased from ~20% to ~80% with the introduction of checkpoint inhibitors

Early suggestions are a 2 year enduring response in ~50% of individuals

Response to immunotherapy continues after drug is stopped due to toxicity and often responses can be seen after initial progression

Very poor prognostic malignancy prior to the introduction of immunotherapy and (for some) targeted agents

Median prognosis was 7 months from diagnosis to death up until the early 2000’s

Chemotherapy had a limited role due to very limited efficacy (ORR 5%)

The Efficacy Triad

•Short Term Response

•Long Term Response

•Enduring Response

Immunotherapy

Melanoma

NSCLC

Renal Cell Carcinoma

Urothelial Malignancies

Head and Neck

Malignancies

Hodgkin Lymphoma

Merkle Cell Carcinoma

3040 Clinical Trials

Triple negative Breast Cancer

Upper GI Malignancies

Malignancies IO is used in

Evolving SettingsM

on

oth

erap

y

Metastatic Disease

1st line

2nd line

3rd line and beyond

Co

mb

inat

ion

Th

erap

y

Metastatic Disease

1st Line

2nd Line

Mo

no

ther

apy

Ther

apy

Mo

no

ther

apy

Ther

apyMaintenance

Locally Advanced

Following Chemoradiotherapy

Adjuvant

Following Surgery

Challenges

• Understanding a rapidly moving field

• Ensuring a patient is treated with the most suitable therapy

• Assessing fitness for therapy

• When to stop ToxicityImmune Related Adverse Events

Immune-Related Adverse Events (irAEs)

Olsson-Brown, Harker. 2018. Guidelines in Practice

Impact on acute medical services

0

20

40

60

80

100

120

140

June 16-Dec 16 Jan 17-June 17 July 17- Dec17 Jan18-June 18

Number of Admissions

The number of IO related admissions to CCC between June 2016 – June 2018

The number of patients receiving IO accessing hotline and triage clinic services between September 2016 – April 2018

Regional IO Service

Immuno-Oncology

Committee (Multiple Key Stakeholders)

Medical Speciality Working Group

Patient information sheets/ App

Education

*E-learning

*Regional teaching

*Info leaflets

Centralised Toxicity

Management process

Oncology delivered/

Co-managed Infliximab delivery

Outpatient IV treatment pathway

Subsequent Toxicity

Protocols

Toxicity Protocols

Single Point of Contact

(24 hour Service)

Fax/ Email Alerts

*ED

*GP

Alert

Cards

Standard Blood Panel

Separated Delivery and Consultant

Review pathways

Standardised IO

Treatment Protocols

On-Treatment

Review Service

(Nurse-led)

IO Team

(Lead nurse, CNS,

Clinicans)

Regional IO Service

The Patient Experience

• Generally well whilst receiving treatment • Can often continue working• Checkmate 024 – QofL and patient experience improved compared to TKI

therapy• Episodes of significant morbidity if a grade 3-4 toxicity is experienced • Hospital stays do occur (particularly in combination therapy)• Often prolonged courses of steroids• Steroid doses are confusing and patients often find this challenging• Often experience more than one toxicity over the course of treatment • Find the reality of toxicity very challenging • The impact of toxicity is very efficacy dependant!

Immunotherapy from the Palliative Care Perspective

Dr Melanie Brooks

Consultant in Palliative Medicine

ImmunotherapyLet start with a summary!

• Immunoglobulin monoclonal antibodies• Potentiate the immune response to tumour cells• Current treatments include ipilimumab, pembrolizumab,

nivolumab, atezolizumab.• IV therapy that can be administered outside of hospital setting• Significantly improving outcomes for a number of metastatic

malignancies• Likely to be a feature of most malignancies within 5 years• May be dependent on tumour marker expression but we don’t

have robust biomarkers as yet

So what do we need to know?

Side effectsFewer side effects during administration

Better tolerated than traditional chemotherapy

• rash and itch

• fatigue and weakness

• cough

• shortness of breath

• nausea and vomiting

• decreased appetite and weight loss

• constipation (or diarrhoea)

• pain (joint, muscle, back, chest, abdominal)

• swelling

• fever

• irregular heartbeat

• infusion-related reactions

• headache

• dizziness

• numbness and tingling

CHALLENGE 1Side effects

Autoimmune Side Effects

• Can occur up to a year later (possibly longer?)

• Even if only 1 cycle of treatment received

• Consider in any patient with previous immunotherapy.

• Significance?

• Potential to forget when faced with familiar palliative signs and symptoms

• Not yet embedded in clinical practice

Adrenal insufficiency versus cancer cachexia anorexia

Other Problems

• Jaundice and Liver Capsular Pain in a patient with known liver metastases– ...

• Increasing SOB in a patient with known lung disease– …

• New onset renal impairment– …

Significance in patients previously treated with Immunotherapy

• Potential confusion over disease progression versus autoimmune disease secondary to treatment.

• Any patient developing fatigue, weight loss (or gain), should have their serum cortisol tested and thyroid function tests as well as LFT, U+E, FBC before a diagnosis of conditional deterioration is made.

• Any patient developing abnormal LFTs needs to be considered as potentially having autoimmune hepatitis.

• Also consider in new renal impairment

• Patients may no longer be under oncologist

Treatment of autoimmune side effects

• Early treatment with high dose steroids is key

• CCC guidance to help manage these patients https://www.clatterbridgecc.nhs.uk/professionals/guidance-1

• Also treatment guidance in SPC for each ICI

• If any of these side effects occur, inform/seek advice from the patient’s oncologist immediately.

CHALLENGE 2Prognosis

Prognosis

• Significant changes in prognosis

• Melanoma, from a less than 30% 1 year survival to over 60% at 2 years and the most recent data suggests ~50% at 4 years (depending on regime)

• NSCLC, from ~35% to over 50% at 1 year

• Improvements in survival also seen many other malignancies such as in renal cell carcinoma, bladder cancer, head and neck tumours, lymphoma….

Enduring response

• Ongoing disease response once treatment stopped.

• Can’t be predicted at individual level

• Contributes to longevity and uncertainty for patients, carers and staff

So what do we do?

• Prognostication will become increasingly difficult

• Communication challenges

• Tissue typing helps in assessing chances of response - increasingly seeing these results in patients records. But even this isn’t certain

• How do we convey this new uncertainty?

• With caution

• How does this affect patients if even we don’t know how to respond to their most difficult questions?

CHALLENGE 3Chronic disease

Increased survival

• Patients are living longer – much longer

• A chronic disease for some?

• Living with cancer

• What are the consequences of this?

– Metastatic disease (palliative diagnosis)

– Symptom burden

– Symptom duration

– Unknown disease progression after treatment ceases

Impact on prescribing

• Palliative drugs (not recommended for chronic illness)

– Danthron

– Potential for tolerance and dependency:

– Opioids

– Benzodiazepines

• Drugs not for long term use

– Senna

– NSAIDs

CHALLENGE 4Steroids

Steroids and treatment

• Patient needs an effective (not supressed) immune system at the time of treatment.

• It is important that steroids are not given around the time of administration of immunotherapy if at all possible.

• If a course of steroids >10mg/24h prednisalone equivalent is considered appropriate, then timing is important. A short course i.e. 5 days could be administered midway between the 2 IV immunotherapy infusions, however– The oncologist needs to be informed

– The response to steroids is documented

– The course not extended without discussion with the oncologist

Steroids and treatment 2

• Enduring response does not appear to be affected by short course steroids and they do not abort an established response to treatment

Summary Product Characteristics and steroid therapy

Drug Systemic corticosteroids beforestarting ICI

After managing immune related side effects

During or after treatment with ICI

NivolumabOPDIVO

‘medicines that suppress your immune system, such as corticosteroids, may interfere with the effect’

‘OPDIVO should not be resumed while the patient is receiving immunosuppressive doses of corticosteroids.’ ‘Withhold dose(s) until management with corticosteroids, is complete’

‘once you are treated with OPDIVO, your doctor may give you corticosteroids to reduce any possible side effects that you may have during your treatment and this will not impact the effect of the medicine.’

PembrolizumabKEYTRUDA

‘should be avoided because of their potential interference with the pharmacodynamic activity and efficacy’

‘KEYTRUDA can be restarted if dose has been reduced to ≤ 10 mg prednisone or equivalent per day.’

No comment

IpilimumabYERVOY

‘should be avoided because of their potential interference with the pharmacodynamic activity and efficacy’

‘YERVOY can be restarted whenmanagement withcorticosteroids is complete’‘do not restart if corticosteroids cannot be reduced to 10 mgprednisone or equivalent per day’

‘The use of systemic corticosteroids after startingipilimumab treatment does not appear to impair the efficacy of ipilimumab.’

CHALLENGE 5Discontinuing treatment

Stopping immunotherapy 1

• Generally well tolerated with little day to day side effects

• Means patients who would not tolerate chemotherapy may still be able to receive immunotherapy.

• There is no clear guidance as to when treatment should be discontinued.

• Future guidance is likely to vary across tumour sites.

Stopping immunotherapy 2

• We may start to see patients wishing to remain on treatment even as they enter the terminal phase of their illness.

• Potential for challenging conversations regarding withdrawal in the deteriorating patient.

• The enduring response of treatment should allow HCPs to support patient and families going through this transition.

Going forward• Steroids – changes in guidance?

• Concomitant use of corticosteroids and immune checkpoint inhibitors has started

• New diagnoses

• 5y prognosis

• Long term immune side effects

• Increasing opioid dependency?

Thank you for Listening

Immunotherapy in Palliative CareCases

Dr Anna Olsson-Brown

MRC Clinical FellowMedical Oncology Registrar

Deputy Chair of the IO Committee, CCC

Case One

• Patient:• Male, 39 y-o, teacher, married, 3 children

• Diagnosis: • Metastatic melanoma (BRAF mutation positive)• 2014- subcutaneous and soft tissue mets• 2016- PD with bone mets, inguinal and iliac lymphadenopathy

• PMH: IBS and depression

• Previous systemic treatment:• 2014 DTIC x 3 cycles• 2015 Ipilimumab x 4 cycles (March – June 2015)- delayed response

• March 2016:– Rapidly progressing LN right groin and new mets in spine– LDH 1300– Prev. considered for 2nd line immunotherapy agent, abandoned. Planned for

targeted treatment (BRAF inhibitor)

• Presentation:– Attended for clinic assessment prior to commencement of BRAF inhibitors in a

wheelchair, G3 fatigue, feeling generally unwell, ↓ PS– Thought to be deteriorating due to disease and approaching the end of his life– Clinic bloods showed a mild AKI and a Sodium 129

• What else would you want to know?

Case One

Case One

• Bloods:– Cortisol < 30 (range 180-600)

– TSH 1.2 mU/L (0.30-5.50)

– Free T4 18.9 pmol/L (11.5-22.7

– Testosterone in the normal range

• Diagnosed with hypoadrenalism

• Started on hydrocortisone replacement

• PS improved from PS3 to PS1

• Commenced combination targeted therapy for melanoma

• Gain 12 months of control from combination therapy

• Very important to consider endocrinopathies as a cause for decline

Case Two

• Patient– 42 year old man, married, owned his own construction business

• Diagnosis – Diagnosed with metastatic renal cell carcinoma in 2016 – Presented with large renal mass, lung metastasis and bone metastasis – Given a prognosis of 12 months at diagnosis

• No prior therapy• Seen by palliative care team for management of pain secondary to bone mets• Benefited from oramorph and was titrated to 90mg Zomorph BD with

breakthrough• At the same time he was enrolled on a clinical trial with Atezolizumab (IO) and

bevacizumab to treat his cancer

Case Two

• 2 years on:

– Complete response to treatment

– No evidence of disease on his latest scan

– Working full time

– Remains on 90mg Zomorph BD for bone pain

– Very reluctant to wean pain relief

Case Three

• Patient– 73 year old lady, retired cleaner, ex-smoker

• Diagnosis– Locally advanced NSCLC in 2017

• Previous treatment– Cisplatin/pemetrexed chemotherapy

• Commenced on pembrolizumab second line following diagnosis of progressive, metastatic disease

• Also referred to Palliative care due to increasing symptoms

Case Three

• Very reluctant to engage with Palliative Care• Has read all the papers about immunotherapy and is convinced that it will cure

her disease• Receives 6 cycles of treatment • Initial scan (after 4 cycles) illustrated essentially stable disease (slight increase in

a couple of areas but insufficient to be PD) and treatment was continued • Despite increasing symptoms of concern very reluctant to discuss her situation

with either palliative care or oncology (for fear of them stopping treatment) • Clear evidence of progressive disease, all IO bloods normal. CT scan illustrates

progressive disease• Huge psychological distress given feelings of loss over outcome from

immunotherapy, discontinuation of treatment and symptomatic decline

CCC website links

• https://www.clatterbridgecc.nhs.uk/professionals/guidance-1

• Immune Related Adverse Event Guideline- Diarrhoea V2.0

• Immune Related Adverse Event Guideline - Endocrinopathies - Adrenal Crisis V1.0

• Immune Related Adverse Event Guideline - Endocrinopathies - Thyroid Dysfunction V1.0

• Immune Related Adverse Event Guideline - Hepatoxicity V2.0

• Immune Related Adverse Event Guideline - Renal Toxicities V2.0

• Immune Related Adverse Event Guideline - Skin Toxicities V2.0

• Immune Related Adverse Event Guideline - Neurological Toxicities V2.0

• Immune Related Adverse Event Guideleine - Pneumonitis V2.0

• Steroid Tapering and Supportive Treatment Guidance V1.0

SPC references

• nivolumab OPDIVO http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/003985/WC500189765.pdf

• Pembrolizumab KEYTRUDA http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/003820/WC500190990.pdf

• Ipilimumab YERVOY http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002213/WC500109299.pdf