(Neo)adjuvant Immunotherapy: The Next Step in Curing Cancer...Immunotherapy Targeted Therapy...
Transcript of (Neo)adjuvant Immunotherapy: The Next Step in Curing Cancer...Immunotherapy Targeted Therapy...
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(Neo)adjuvant Immunotherapy: The Next Step in Curing Cancer
Davey Daniel, MD
1/11/2019
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Disclosures
No direct conflicts of interest
Sarah Cannon Research: ER Squibb, AstraZeneca, Boehringer Ingleheimer, Genetech, Eli Lilly and Company, Novartis, Pfizer, Celgene
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Today’s Objectives
Identify alternative endpoints for development of cancer therapy
Neoadjuvant therapy is an increasing standard of care for many tumors.
Adjuvant immunotherapy is now a standard treatment in melanoma. Neoadjuvant therapy may be a new standard in breast cancer.
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Immunotherapy – Checkpoint Inhibition
https://www.cancer.gov/publications/dictionaries/cancer-
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Immunotherapy Toxicity
https://cancerworld.net/e-grandround/management-of-toxicities-related-to-immunotherapies/
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Searching for Predictors of Response
https://www.philipchircop.com/post/25783275888/seeing-the-full-elephant-its-a-tree-its-a
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AdjuvantImmunotherapy
• Standard of care in stage III/IV resected melanoma
• Other cancers: Jury is out
LU N G C A N C E R K I D N E Y C A N C E R B L A D D E R C A N C E R
IMPOWER 010 (Atezolizumab)10/2015
PROSPER RCC (Nivolumab)ONGOING
Imvigor0101 (Atezolizumab)
KEYNOTE 091 – PEARLS Pembrolizumab 11/2015
Nivolumab +/- IpilumumabOngoing
Checkmate 274 (Nivolumab)2/2016 (completed)
ANVIL trial (Nivolumab)5/2016
MK3475 (Pembrolizumab)COMPLETED
AMBASSADOR (Pembrolizumab)
Durvalumab 11/2014
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Adjuvant Melanoma Therapy- Keynote 054
AM Eggermont et al. N Engl J Med 2018;378:1789-1801.
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Adjuvant Immunotherapy – Checkmate 238
Weber J et al. N Engl J Med 2017;377:1824-1835.
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Neoadjuvant therapy as surrogate endpoint
• Pathological Complete Response and Accelerated Drug Approval in Early Breast Cancer
• T Prowell MD, R. Pazdur MD N Engl J Med 2012; 366:2438-2441
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Rationale for Neoadjuvant Immunotherapy
Tumor Shrinkage –Decreasing morbidity
More effective therapeutic
treatment of distant micro-metastatases
Delays are important
New drug development
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Timing matters
Weber J et al. N Engl J Med 2017;377:1824-1835.
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Melenoma -Neoadjuvant
ASCO 2019 – International Neoadjuvant Melanoma Consortium Meta-analysis
• 6 trials of Neoadjuvant therapy
• 184 patients (133 immunotherapy / 55 targeted
Immunotherapy Targeted Therapy
Pathologic Complete Response (pCR)
38% 47%
12m PFS 83% 65%
pCR Recurrences 0 /51 7/17
Non-pCR Recurrence 18/82 19/27
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Neoadjuvant Breast Cancer
2 trials presented in December 2019
Divergent conclusions
Stage and pathology
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NeoTRIPMichaelangeloTrial
•Triple negative breast cancer (ER-,PR-, Her2-)
•N1 Node + or large mass
Population:
•Carboplatin / nab-paclitaxel
•Carboplatin / nab- paclitaxel / atezolizumab
Treatment - 8 cycles of neoadjuvant chemotherapy
•Event Free Survival
•Pathologic complete response
Endpoints
NeoTripaPDL1 Michaelango TrialLuco Gianni et a. San Antonio Breast Conference 2019.
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Results – Pathologic Complete Response
Chemotherapy + Atezolizumab
Chemotherapy
# of patients 138 142
Path Complete Responses
43.5% 40.8%
Odds ratio 1.11 (0.69-1.79)
NeoTripaPDL1 Michaelango TrialLuco Gianni et a. San Antonio Breast Conference 2019.
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KEYNOTE-522
•Followed by Adjuvant Pembrolizumab versus Placebo for Early Triple Negative Breast Cancer
Phase 3 trial of Neoadjuvant
Pembrolizumab with
chemotherapy
•N1 or N2 disease
Higher risk patients included:
•Chemotherapy for 4 cycles (Carboplatin / paclitaxel) then Epirubicin / Cyclophosphamide x 4 cycles +/- Pembrolizumab
•Surgery
•Pembrolizumab or placebo x 8 cycles
Treatment
Peter Schmid et al. San Antonio Breast Cancer Symposium December 2019
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Keynote-522
0
10
20
30
40
50
60
70
Pembro/ChemoPlacebo/Chemo
Pathologic Complete response 64.8 51.2
64.8
51.2
PATHOLOGIC COMPLETE RESPONSE
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Response by Stage
73.1
56.2
66.7
48.6
62.1
48.4
42.1
23.1
0
10
20
30
40
50
60
70
80
Stage IIA Stage IIB Stage IIIA Stage IIIB
Chart Title
Pembro + Chemo Placebo + Chemo
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Neoadjuvant Lung Cancer
• Surgically Operable stage I or II Non-Small cell cancer
• 2 doses of Nivolumab (4 weeks)
• Endpoint: Major Pathologic Response (<10% residual tumor)
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Results
• No significant toxicity
• 9/21 patient had MPR
• Major Pathologic Response
<10% viable cancer cells
PM Forde et al. N Engl J Med 2018;378:1976-1986.
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• Subjects will be randomized to one of four treatment arms
• Additional arms may be added in the future
NeoCOAST – Study Design
22
Durva (n=40)
Durva + CD73 (n=40)
Durva + NKG2A (n=40)
Durva + STAT3 (n=40)
Durva + X (n=40)
Resectable NSCLC Stage I-IIIA(N0-1)
Primary endpoints: MPR
Secondary endpoints:• Feasibility to Surgery
• Pathological Complete Response (pCR)
• ORR, safety, PK, immunogenicity
Exploratory endpoints:• ctDNA, TMB, TILs, IFN-g signature, etc
Treatment (28 days) – (Danvatirsen Arm -7 day lead in period )
Ran
do
miz
atio
n
Screening(up to 21 days)
Dx
Surg
ery
Imaging Imaging
Day 29-42
FUP/ EOS Up to Day 105
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NeoCoast Trial at Memorial
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Neoadjuvant Bladder
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Summary
• Adjuvant and neoadjuvant therapy now standard in some cases.
• Adjuvant Stage III melanoma.
• Neoadjuvant in SOME breast patients.
• Answers will vary.
• Trials are the key.