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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.