Immunotherapy: Treatment Response and Toxicities · What about in breast cancer? –Most data is in...

Immunotherapy:

Treatment Response and

Toxicities

Mark Harries

Immunotherapy

• Long History

– Coley’s Toxin

– IFN/IL-2

– Adoptive T cell therapy

INTERLEUKIN 2 Atkins 1999

Immunotherapy

• Now:

– Anti CTLA-4

– Anti PD-1 and PD-L1

– TIL

– CAR-T

Checkpoint Blockade

Immunotherapy

– Anti CTLA-4

– Anti PD-1 and PD-L1

– CONSIDERABLE SUCCESS IN A RANGE OF

TUMOUR TYPES

What about in breast cancer?

– Most data is in TNBC:

● Very modest response rates as a single agent

● Poor response rates in heavily pre-treated patients

● Occasional durable responses seen in Phase 1/2

● Better efficacy in the PD-L1 positive population

– At least with atezolizumab in MBC

Atezolizumab TNBC early phase

• 115 patients

• Response rate:

• First-line - 5 of 21 (24%)

• Second or subsequent - 6 of 94 (6%)

Pembrolizumab TNBC Early Phase

–previously treated

• 170 patients

• Approx 50% > 3 lines

• ORR 5.3% in the total group

•

Pembrolizumab TNBC Early Phase

First-Line

• 84 patients First-Line

• ORR of 21.4% (95% CI, 13.9-31.4)

Atezolizumab and Nab-Paclitaxel in Advanced Triple-Negative Breast Cancer

Peter Schmid, M.D., Ph.D., Sylvia Adams, M.D., Hope S. Rugo, M.D., Andreas Schneeweiss, M.D., Carlos H. Barrios, M.D., Hiroji Iwata, M.D., Ph.D., Véronique

Diéras, M.D., Roberto Hegg, M.D., Seock-Ah Im, M.D., Ph.D., Gail Shaw Wright, M.D., Volkmar Henschel, Ph.D., Luciana Molinero, Ph.D., Stephen Y.

Chui, M.D., Roel Funke, Ph.D., Amreen Husain, M.D., Eric P. Winer, M.D., Sherene Loi, M.D., Ph.D., Leisha A. Emens, M.D., Ph.D., for the IMpassion130 Trial

Investigators

N Engl J MedVolume 379(22):2108-2121

November 29, 2018

Kaplan–Meier Analysis of Progression-free Survival and Overall Survival.

Schmid P et al. N Engl J Med 2018;379:2108-2121

ITT:

PFS 7.2 months vs. 5.5 months

HR 0.8 P=0.002

OS 21.3 months vs.17.6 months

HR 0.84 P=0.08

PD-L1–positive group:

PFS 7.5 months and 5.0 months

HR 0.62 P<0.001

OS 25.0 months and 15.5 months

HR 0.62 – no P value*

*result could not be formally tested due to the prespecified statistical testing

hierarchy.Schmid et al. N Engl J MedVolume 379(22):2108-2121

November 29, 2018

Any Grade Adverse Events of Special Interest:

Rash 34 vs 26 %

Thyroid 22 vs 6

Hepatitis 16 vs 15

Pneumonitis 3 vs 0.2

Meningoencephalitis 1 vs 0.5

Colitis 1 vs 0.7

Adrenal insufficiency 0.9 vs 0

Pancreatitis 0.4 vs 0

DBM 0.2 vs 0.5

Nephritis 0.2 vs 0

IMpassion 131

• Follow-up study

• Control arm is paclitaxel

• 2:1 randomisation

• 3

IMpassion 132

• Early relapse

• Control arm is gem/carbo or cape

• 2:1 randomisation

• 3

Phase 3 TNBC Pembrolizumab Study

• KEYNOTE-355: Randomized, double-blind, phase III study of pembrolizumab +chemo vs placebo (PBO) + chemo for previously untreated, locally recurrent, inoperable or metastatic triple-negative breast cancer

• 3 chemo arms (abraxane, pacli, gem/carbo)

• Stratification for PDL-1 expression

• ? Later in 2020• 3

KEYNOTE-522 Neoadjuvant Phase 3 Pembrolizumab

Study –ESMO 2019

• 1,174 patients randomised:

• 2:1 ratio to pembrolizumab or placebo

– added to neoadjuvant chemotherapy with anthracyclines,

taxanes, and platinum,

• After surgery: treatment of pembrolizumab or placebo

for nine cycles.

• Median follow-up of 15.5 months.

KEYNOTE-522 Neoadjuvant Phase 3 Pembrolizumab

Study –ESMO 2019

• Path CR, assessed in the first 602 patients:

• 51.2% (95% CI 44.1–58.3) in the placebo group

• 64.8% (95% CI 59.9–69.5) in the pembrolizumab

group (p=0.00055).

• 13.6% difference

KEYNOTE-522 Neoadjuvant Phase 3 Pembrolizumab

Study –ESMO 2019

• 68.9% vs 54.9% in the PD-L1+ population

• 45.3% vs 30.3% in the PD-L1- population

KEYNOTE-522 Neoadjuvant Phase 3 Pembrolizumab

Study –ESMO 2019

• Interim analysis of event-free survival.

• There was a favourable trend for the pembrolizumab

group with a hazard ratio of 0.63 (95% CI 0.43–0.93),

Where are we for IO in TNBC?

• Atezolizumab

– Clinically relevant activity in PDL-1 positive MBC TNBC

Pembrolizumab

Genuine Promise when added to NACT for TNBC

Biomarkers not perfect

Assessing response to Immunotherapy

Control

Chemo or targeted therapies

Su

rviv

al

Time

Su

rviv

al

Time

Conventional anticancer

therapyImmunotherapy

Median survival no longer the outcome measure?

Control

Immune checkpoint blockade

Adapted from Paz-Ares, ESMO 2014

Need a measure of

long term survival

Kaplan–Meier Analysis of Progression-free Survival and Overall Survival.

Schmid P et al. N Engl J Med 2018;379:2108-2121

Immune-Related Response CriteriaWolchok et al. CCR 2009

Practical Aspects of Delivery of Immunotherapy

• The iv delivery of the drugs and need for clinical assessment prior to Rx will be very familiar to Breast Oncologists

What to look out for:

• The expected:• Fatigue• Skin Rash• Endocrinopathies• Hepatitis (chemo or IO?)

• Rarer:• Arthralgia• Colitis• Nephritis• Pneumonitis

Clinical assessment prior to Rx needs to include evaluation of low grade IO toxicities

• Symptoms:

• Fatigue

• Dry mouth

• Diarrhoea

• Rash

• Endocrinopathies

• Bloods to include:

• TSH,fT4

• Cortisol

• Glucose

What to look out for:

The unexpected e.g.:

Myocarditis

Type 1 DBM

Bullous pemphoid

Management of anti PD-1/PD-L1 related toxicities

• Early recognition and intervention key

Overarching guidance

• ESMO guidance on treatment of immunotherapy toxicities

• UKONS immediate AOS management guidance

• NCCN Management of Immunotherapy-Related Toxicities

For example:

Adverse reactions Monitoring patients Ask patients to immediately report

Immune-mediatedpneumonitis

• Monitor patients for signs and symptomsof pneumonitis.• If pneumonitis is suspected, evaluate withradiographic imaging.

• Shortness of breath• Chest pain• New or worsening cough

Immune-mediated colitis • Monitor patients for signs and symptoms of colitis.

• Diarrhoea • Stools that are black, tarry, sticky, or have blood or mucus• Severe stomach-area (abdomen) pain or tenderness

Immune-mediatedendocrinopathies

Monitor patients for signs and symptomsof hypophysitis, hypopituitarismand adrenal insufficiency.•Monitor patients forchanges in thyroid function and for signs and symptoms ofthyroid disorders.• Monitor patients for symptoms of hyperglycaemia

• Rapid heart beat• Weight loss or weight gain• Increased sweating• Feeling more hungry or thirsty• Urinating more often than usual• Hair loss• Feeling cold• Constipation• Deepened voice• Muscle aches• Dizziness or fainting• Headaches that will not go away or unusual

IMMUNE CHECKPOINT INHIBITOR (ICPi)-RELATED TOXICITY: MANAGEMENT OF DIARRHOEA & COLITIS

Prednisolone 0.5-1mg/kg (non-enteric coated) OR consider oral budesonide 9mg OD if no bloody diarrhoeaDo not wait for sigmoidoscopy to start

Symptomatic Mx: oral fluids, loperamide, avoid high fibre/lactose dietEnsure patient has CNS contact

details

IV methylprednisolone 1-2mg/kg Gastroenterology input and ensure sigmoidoscopy is requested

Infliximab 5mg/kg (if no perforation/sepsis/TB/hepatitis/NYHA III/IV CCF)Can repeat 2 weeks later(use mycophenylate if concomitant hepatitis)Must have had flex sigmoidoscopy & Gastroenterology review prior See attached infliximab safety checklist

Symptom Grade Management escalation pathway Assessment & Investigations

Mild (G1): ie <3 liquid stools per day over baseline, feeling wellICPi can be continued

Moderate (G2): ie 4-6 liquid stools per day over baseline OR abdo pain OR blood in stool OR nausea OR nocturnal episodesOutpatient management if appropriateIf unwell, manage as per severeICPi to be witheld

Severe (G3/4): ie >6 liquid stools per day over baseline OR if episodes within 1hr eating Requires hospitalisation and isolation until infection excluded

ICPi to be witheld

G1 and persists >14 days OR G2 and persists for >3 days OR worsens

No improvement in 72 hours OR worsening OR absorption concern

No improvement in 72 hours OR worsening

Baseline Investigations: FBC, UEC, LFT, CRP, TFTsStool microscopy for leucocytes/ova/parasites, culture, viral PCR, C. diff toxin & cryptosporidiaAlso culture for drug-resistant organismsGive patient Bristol stool chart for stool gradeOutpatients: Baseline Ix as aboveAXR for signs of colitisExclude steatorrhoeaBook sigmoidoscopy (+/- biopsy) & OGDContact patient every 72 hoursRepeat baseline bloods at outpatient review

Inpatients: Ix as above, including sigmoidoscopyCT Abdo/Pelvis, repeat AXR as indicatedDaily FBC, UEC, LFT, CRPReview diet (eg NBM, clear fluids, TPN)Early surgical review if bleeding, pain or distensionSteroid wean duration:

• Moderate: wean over 2-4 wks• Severe: wean over 4-8 wksSteroids >4 weeks:Consider PJP prophylaxis, regular random blood glucose, vitamin D level, start calcium/Vit D supplement

Medications:Prednisolone 100mg = Methylprednisolone 80mg (ie 5:4 ratio)Loperamide 4mg 1st dose then 2mg 30mins before each meal and after each loose stool until 12hrs without diarrhoea (max 16mg/day)

At clinician discretion

Management of IO related Toxicities

• Grade 2/3 – stop the IO drug

• Early introduction of steroids –e.g. prednisolone 1-2mg/kg

• Consider IV methyl pred

• Slow taper of steroids

• ‘ology’ help

• Endocrine replacement if needed

• Can resume IO if grade 1 or less (not if was severe)

• If not resolving/worsening:

• Infliximab

• Mycophenolate

Build a network of interested ‘ologists’

• Gastroenter..

• Endocrin..

• Dermat..

• Hepatol..

• Rhematol..

• Neurolo..

• Nephrolo..

• Pulmono..

Upskill the team

CNS SpRs AOS

Case Histories

Patient VW – mid 50’s

Anti PD-1 for melanoma

Arrives in clinic ‘tired’

Cortisol comes back v low

Starts HC –immediate

improvement

Case Histories

Patient CR – mid 50’s Anti PDL-1 for metastatic breast ca

Arrives in clinic ‘tired’

Cortisol comes back v low

But no improvement:

Why?

Case Histories

ON STEROIDS PD

Case Histories

Patient MR – mid 70’s

Anti PD-1 for melanoma

Phones AOS with diarrhoea

Advised to take Loperamide

No assessment of severity, no call back to see progress

What happens next….

Case Histories

• long hospital admission with colitis

Challenge

Education of AOS and other

disciplines

Dissecting IO from Chemo

related toxicities

Summary

Immunotherapy is arriving at a breast clinic near you!

More and more data coming

• ER pos HER2 pos

Assessment of treatment response and toxicity is different

• Needs education, team work and experience.